The hippocampus supports the representation of abstract concepts: Implications for the study of recognition memory.

Words, unlike images, are symbolic representations. The associative details inherent within a word's meaning and the visual imagery it generates, are inextricably connected to the way words are processed and represented. It is well recognised that the hippocampus associatively binds components of a memory to form a lasting representation, and here we show that the hippocampus is especially sensitive to abstract word processing. Using fMRI during recognition, we found that the increased abstractness of words produced increased hippocampal activation regardless of memory outcome. Interestingly, word recollection produced hippocampal activation regardless of word content, while the parahippocampal cortex was sensitive to concreteness of word representations, regardless of memory outcome. We reason that the hippocampus has assumed a critical role in the representation of uncontextualized abstract word meaning, as its information-binding ability allows the retrieval of the semantic and visual associates that, when bound together, generate the abstract concept represented by word symbols. These insights have implications for research on word representation, memory, and hippocampal function, perhaps shedding light on how the human brain has adapted to encode and represent abstract concepts.

Assessment of non-directed computer-use behaviours in the home can indicate early cognitive impairment: A proof of principle longitudinal study.

OBJECTIVES: Computer-use behaviours can provide useful information about an individual's cognitive and functional abilities. However, little research has evaluated unaided and non-directed home computer-use. In this proof of principle study, we explored whether computer-use behaviours recorded during routine home computer-use i) could discriminate between individuals with subjective cognitive decline (SCD) and individuals with mild cognitive impairment (MCI); ii) were associated with cognitive and functional scores; and iii) changed over time. METHODS: Thirty-two participants with SCD (n = 18) or MCI (n = 14) (mean age = 72.53 years; female n = 19) participated in a longitudinal study in which their in-home computer-use behaviour was passively recorded over 7-9 months. Cognitive and functional assessments were completed at three time points: baseline; mid-point (4.5 months); and end point (month 7 to 9). RESULTS: Individuals with MCI had significantly slower keystroke speed and spent less time on the computer than individuals with SCD. More time spent on the computer was associated with better task switching abilities. Faster keystroke speed was associated with better visual attention, recall, recognition, task inhibition, and task switching. No significant change in computer-use behaviour was detected over the study period. CONCLUSION: Passive monitoring of computer-use behaviour shows potential as an indicator of cognitive abilities, and can differentiate between people with SCD and MCI. Future studies should attempt to monitor computer-use behaviours over a longer time period to capture the onset of cognitive decline, and thus could inform timely therapeutic interventions.Supplemental data for this article can be accessed online at http://dx.doi.org/10.1080/13607863.2022.2036946.

Experiencing Surprise: The Temporal Dynamics of Its Impact on Memory.

To efficiently process information, the brain shifts between encoding and retrieval states, prioritizing bottom-up or top-down processing accordingly. Expectation violation before or during learning has been shown to trigger an adaptive encoding mechanism, resulting in better memory for unexpected events. Using fMRI, we explored (1) whether this encoding mechanism is also triggered during retrieval, and if so, (2) what the temporal dynamics of its mnemonic consequences are. Male and female participants studied object images, then, with new objects, they learned a contingency between a cue and a semantic category. Rule-abiding (expected) and violating (unexpected) targets and similar foils were used at test. We found interactions between previous and current similar events' expectation, such that when an expected event followed a similar but unexpected event, its performance was boosted, underpinned by activation in the hippocampus, midbrain, and occipital cortex. In contrast, a sequence of two unexpected similar events also triggered occipital engagement; however, this did not enhance memory performance. Taken together, our findings suggest that when the goal is to retrieve, encountering surprising events engages an encoding mechanism, supported by bottom-up processing, that may enhance memory for future related events.SIGNIFICANCE STATEMENT Optimizing the balance between new learning and the retrieval of existing knowledge is an ongoing process, at the core of human cognition. Previous research into memory encoding suggests experiencing surprise leads to the prioritization of the learning of new memories, forming an adaptive encoding mechanism. We examined whether this mechanism is also engaged when the current goal is to retrieve information. Our results demonstrate that an expectation-driven shift toward an encoding state, supported by enhanced perceptual processing, is beneficial for the correct identification of subsequent expected similar events. These findings have important implications for our understanding of the temporal dynamics of the adaptive encoding of information into memory.

Cognitive impairment in patients with moderate to severe chronic kidney disease: the Salford kidney cohort study.

BACKGROUND: Cognitive impairment in chronic kidney disease (CKD) is common and underrecognized [1, 2]. Determining risk factors for cognitive impairment and whether speed of CKD progression is an important consideration may help identify cognitive impairment by nephrologists. Vascular disease is thought to underpin cognitive impairment in CKD and by segregating CKD patients with proven vascular disease, we may also be able to discover other important associations with cognitive impairment in CKD patients. METHOD: A total of 250 patients in a UK prospective cohort of CKD patients underwent two cognitive assessments: Montreal Cognitive Assessment test and Trail Making Test. Cognitive impairment was defined using validated population cut-offs (cognitive impairment) and relative cognitive impairment. Relative cognitive impairment was defined by <1 standard deviation below the mean Z-score on any completed test. Two multivariable logistical regression models identified variables associated with cognitive impairment and realtive cognitive impairment. RESULTS: About 44 and 24.8% of patients suffered cognitive impairment and relative cognitive impairment, respectively. Depression, previous stroke and older age were significantly associated with cognitive impairment. Older age was significantly associated with relative cognitive impairment (P ≤ 0.05) and higher proteinuria and the use of psychodynamic medications were also significantly associated with relative cognitive impairment (P = 0.05). Delta estimated glomerular filtration rate (eGFR) in patients with cognitive impairment and relative cognitive impairment compared with those having normal cognition was similar (-0.77 versus -1.35 mL/min/1.73 m2/year, P = 0.34 for cognitive impairment and -1.12 versus -1.02 mL/min/1.73 m2/year, P = 0.89 for relative cognitive impairment). CONCLUSION: Risk factors for cognitive impairment in CKD include previous stroke, depression or anxiety, higher proteinuria and prescription of psychodynamic medications. Patients with a faster eGFR decline do not represent a group of patients at increased risk of cognitive impairment.

Can pupillometry distinguish accurate from inaccurate familiarity?

Pupillometry, the measurement of pupil diameter, has become increasingly popular as a tool to investigate human memory. It has long been accepted that the pupil is able to distinguish familiar from completely novel items, a phenomenon known as "pupil old/new effect". Surprisingly, most pupillometric studies on the pupil old/new effect tend to disregard the possibility that the pupillary response to familiarity memory may not be entirely exclusive. Here, we investigated whether the pupillary response to old items correctly judged familiar (hits; accurate familiarity) can be differentiated from the pupillary response to new items wrongly judged familiar (false alarms; inaccurate familiarity). We found no evidence that the two processes could be isolated, as both accurate and inaccurate familiarity showed nearly identical mean and across-time pupillary responses. However, both familiarity hits and false alarms showed pupillary responses unequivocally distinct from those observed during either recollection or novelty detection, which suggests that the pupil measure of familiarity hits and/or false alarms was sufficiently sensitive. The pupillary response to false alarms may have been partially driven by perceptual fluency, since novel objects incorrectly judged to be old (i.e., false alarms) showed a higher degree of similarity to studied images than items correctly judged as novel (i.e., correct rejections). Thus, our results suggest that pupil dilation may not be able to distinguish accurate from inaccurate familiarity using standard recognition memory paradigms, and they also suggest that the pupillary response during familiarity feelings may also partly reflect perceptual fluency.

A reassessment of the pseudoneglect effect: Attention allocation systems are selectively engaged by semantic and spatial processing.

Healthy individuals display systematic inaccuracies when allocating attention to perceptual space. Under many conditions, optimized spatial attention processing of the right hemisphere's frontoparietal attention network directs more attention to the left side of perceptual space than the right. This is the pseudoneglect effect. We present evidence reshaping our fundamental understanding of this neural mechanism. We describe a previously unrecognized, but reliable, attention bias to the right side of perceptual space that is associated with semantic object processing. Using an object bisection task, we revealed a significant rightward bias distinct from the leftward bias elicited by the traditional line bisection task. In Experiment 2, object-like shapes that were not easily recognizable exhibited an attention bias between that of horizontal lines and objects. Our results support our proposal that the rightward attention bias is a product of semantic processing and its lateralization in the left hemisphere. In Experiment 3, our novel object-based adaptation of the landmark task further supported this proposition and revealed temporal dynamics of the effect. This research provides novel and crucial insight into the systems supporting intricate and complex attention allocation and provides impetus for a shift toward studying attention in ways that increasingly reflect our complex environments. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Enhancing 'meaningfulness' of functional assessments: UK adaptation of the Amsterdam IADL questionnaire.

OBJECTIVE: Commonly used measures of instrumental activities of daily living (IADL) do not capture activities for a technologically advancing society. This study aimed to adapt the proxy/informant-based Amsterdam IADL Questionnaire (A-IADL-Q) for use in the UK and develop a self-report version. DESIGN: An iterative mixed method cross-cultural adaptation of the A-IADL-Q and the development of a self-report version involving a three-step design: (1) interviews and focus groups with lay and professional stakeholders to assess face and content validity; (2) a questionnaire to measure item relevance to older adults in the U.K.; (3) a pilot of the adapted questionnaire in people with cognitive impairment. SETTING: Community settings in the UK. PARTICIPANTS: One hundred and forty-eight participants took part across the three steps: (1) 14 dementia professionals; 8 people with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or dementia due to Alzheimer's disease; and 6 relatives of people with MCI or dementia; (2) 92 older adults without cognitive impairment; and (3) 28 people with SCD or MCI. MEASUREMENTS: The cultural relevance and applicability of the A-IADL-Q scale items were assessed using a 6-point Likert scale. Cognitive and functional performance was measured using a battery of cognitive and functional measures. RESULTS: Iterative modifications to the scale resulted in a 55-item adapted version appropriate for UK use (A-IADL-Q-UK). Pilot data revealed that the new and revised items performed well. Four new items correlated with the weighted average score (Kendall's Tau -.388, -.445, -.497, -.569). An exploratory analysis of convergent validity found correlations in the expected direction with cognitive and functional measures. CONCLUSION: The A-IADL-Q-UK provides a measurement of functional decline for use in the UK that captures culturally relevant activities. A new self-report version has been developed and is ready for testing. Further evaluation of the A-IADL-Q-UK for construct validity is now needed.

Mid to late-life scores of depression in the cognitively healthy are associated with cognitive status and Alzheimer's disease pathology at death.

OBJECTIVES: Early diagnosis of Alzheimer's disease (AD) is essential for early interventions. Symptoms of depression could represent a prodromal stage of AD. Very early mood alterations may help to stratify those at highest risk of late-life AD. We aim to investigate associations between baseline/longitudinal scores for depression, presence of cognitive impairment and/or AD pathology at death. METHODS/DESIGN: Between 1991 and 2015, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent 10 waves of assessment using the Geriatric Depression Scale (GDS). AD pathology at death was evaluated in 106 eligible cases. Analyses aimed to examine associations between GDS scores, cognitive status and AD pathology (as measured by Braak stage, Thal phase and CERAD). RESULTS: Baseline GDS scores were significantly higher for those cognitively impaired at death than those cognitively normal. Significantly higher baseline GDS scores were found for those with greater Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores than those with lower CERAD scores. Similarly, significantly higher baseline GDS scores were found for those with a greater Braak stage than those with lower tau burden. These correlations remained after controlling for age at death, education and APOE ε4, but were less robust. Mean longitudinal GDS scores associated with cognition but not pathology. CONCLUSIONS: GDS scores collected approximately 20 years before death were associated with cognitive status and AD pathology at death. We postulate that early AD-related pathological change produces raised GDS scores due to an overlapping neural basis with depression, and that this may be considered as an early diagnostic marker for AD.

Information content best characterises the hemispheric selectivity of the inferior parietal lobe: a meta-analysis.

Our understanding of the inferior parietal lobe (IPL) remains challenged by inconsistencies between neuroimaging and neuropsychological perspectives. To date, others assume that hemispheric specialisation of the IPL is linked with the type of processing; attention processing in the right hemisphere; memory retrieval and semantic judgement in the left hemisphere. Here, we provide compelling evidence associating the type of information being processed with the recruitment of each hemisphere's IPL. In a meta-analysis, we classify 121 previous fMRI reports of IPL activity arising from episodic memory retrieval, according to the type of information that characterises each fMRI contrast. We demonstrate that the left IPL is more consistently associated with retrieval of the semantic (95% of eligible contrasts) than perceptual aspects of memory (83%). In contrast, the right IPL is more consistently associated with the retrieval of perceptual (97%), than semantic aspects of memory (43%). This work revises assumptions of how the IPL contributes to healthy cognition and has major implications for IPL-related neuropsychological deficits.

Detection of scene-relative object movement and optic flow parsing across the adult lifespan.

Moving around safely relies critically on our ability to detect object movement. This is made difficult because retinal motion can arise from object movement or our own movement. Here we investigate ability to detect scene-relative object movement using a neural mechanism called optic flow parsing. This mechanism acts to subtract retinal motion caused by self-movement. Because older observers exhibit marked changes in visual motion processing, we consider performance across a broad age range (N = 30, range: 20-76 years). In Experiment 1 we measured thresholds for reliably discriminating the scene-relative movement direction of a probe presented among three-dimensional objects moving onscreen to simulate observer movement. Performance in this task did not correlate with age, suggesting that ability to detect scene-relative object movement from retinal information is preserved in ageing. In Experiment 2 we investigated changes in the underlying optic flow parsing mechanism that supports this ability, using a well-established task that measures the magnitude of globally subtracted optic flow. We found strong evidence for a positive correlation between age and global flow subtraction. These data suggest that the ability to identify object movement during self-movement from visual information is preserved in ageing, but that there are changes in the flow parsing mechanism that underpins this ability. We suggest that these changes reflect compensatory processing required to counteract other impairments in the ageing visual system.

Pattern Separation Underpins Expectation-Modulated Memory.

Pattern separation and completion are fundamental hippocampal computations supporting memory encoding and retrieval. However, despite extensive exploration of these processes, it remains unclear whether and how top-down processes adaptively modulate the dynamics between these computations. Here we examine the role of expectation in shifting the hippocampus to perform pattern separation. In a behavioral task, 29 participants (7 males) learned a cue-object category contingency. Then, at encoding, one-third of the cues preceding the to-be-memorized objects, violated the studied rule. At test, participants performed a recognition task with old objects (targets) and a set of parametrically manipulated (very similar to dissimilar) foils for each object. Accuracy was found to be better for foils of high similarity to targets that were contextually unexpected at encoding compared with expected ones. Critically, there were no expectation-driven differences for targets and low similarity foils. To further explore these effects, we implemented a computational model of the hippocampus, performing the same task as the human participants. We used representational similarity analysis to examine how top-down expectation interacts with bottom-up perceptual input, in each layer. All subfields showed more dissimilar representations for unexpected items, with dentate gyrus (DG) and CA3 being more sensitive to expectation violation than CA1. Again, representational differences between expected and unexpected inputs were prominent for moderate to high levels of input similarity. This effect diminished when inputs from DG and CA3 into CA1 were lesioned. Overall, these novel findings strongly suggest that pattern separation in DG/CA3 underlies the effect that violation of expectation exerts on memory.SIGNIFICANCE STATEMENT What makes some events more memorable than others is a key question in cognitive neuroscience. Violation of expectation often leads to better memory performance, but the neural mechanism underlying this benefit remains elusive. In a behavioral study, we found that memory accuracy is enhanced selectively for unexpected highly similar foils, suggesting expectation violation does not enhance memory indiscriminately, but specifically aids the disambiguation of overlapping inputs. This is further supported by our subsequent investigation using a hippocampal computational model, revealing increased representational dissimilarity for unexpected highly similar foils in DG and CA3. These convergent results provide the first evidence that pattern separation plays an explicit role in supporting memory for unexpected information.

Thalamic-Medial Temporal Lobe Connectivity Underpins Familiarity Memory.

The neural basis of memory is highly distributed, but the thalamus is known to play a particularly critical role. However, exactly how the different thalamic nuclei contribute to different kinds of memory is unclear. Moreover, whether thalamic connectivity with the medial temporal lobe (MTL), arguably the most fundamental memory structure, is critical for memory remains unknown. We explore these questions using an fMRI recognition memory paradigm that taps familiarity and recollection (i.e., the two types of memory that support recognition) for objects, faces, and scenes. We show that the mediodorsal thalamus (MDt) plays a material-general role in familiarity, while the anterior thalamus plays a material-general role in recollection. Material-specific regions were found for scene familiarity (ventral posteromedial and pulvinar thalamic nuclei) and face familiarity (left ventrolateral thalamus). Critically, increased functional connectivity between the MDt and the parahippocampal (PHC) and perirhinal cortices (PRC) of the MTL underpinned increases in reported familiarity confidence. These findings suggest that familiarity signals are generated through the dynamic interaction of functionally connected MTL-thalamic structures.

SOLID-Similar object and lure image database.

Stimulus selection is a critical part of experimental designs in the cognitive sciences. Quantifying and controlling item similarity using a unified scale provides researchers with the tools to eliminate item-dependent effects and improve reproducibility. Here we present a novel Similar Object and Lure Image Database (SOLID) that includes 201 categories of grayscale objects, with approximately 17 exemplars per set. Unlike existing databases, SOLID offers both a large number of stimuli and a considerable range of similarity levels. A common scale of dissimilarity was obtained by using the spatial-arrangement method (Exps. 1a and 1b) as well as a pairwise rating procedure to standardize the distances (Exp. 2). These dissimilarity distances were then validated in a recognition memory task, showing better performance and decreased response times as dissimilarity increased. These methods were used to produce a large stimulus database (3,498 images) with a wide range of comparable similarities, which will be useful for improving experimental control in fields such as memory, perception, and attention. Enabling this degree of control over similarity is critical for high-level studies of memory and cognition, and combining this strength with the option to use it across many trials will allow research questions to be addressed using neuroimaging techniques.

Which computer-use behaviours are most indicative of cognitive decline? Insights from an expert reference group.

Computer use is becoming ubiquitous among older adults. As computer use depends on complex cognitive functions, measuring individuals' computer-use behaviours over time may provide a way to detect changes in their cognitive functioning. However, it is uncertain which computer-use behaviour changes are most likely to be associated with declines of particular cognitive functions. To address this, we convened six experts from clinical and cognitive neurosciences to take part in two workshops and a follow-up survey to gain consensus on which computer-use behaviours would likely be the strongest indicators of cognitive decline. This resulted in a list of 21 computer-use behaviours that the majority of experts agreed would offer a 'strong indication' of decline in a specific cognitive function, across Memory, Executive function, Language and Perception and Action domains. This list enables a hypothesis-driven approach to analysing computer-use behaviours predicted to be markers of cognitive decline.

Amount, not strength of recollection, drives hippocampal activity: A problem for apparent word familiarity-related hippocampal activation.

The role of the hippocampus in recollection and familiarity remains debated. Using functional magnetic resonance imaging (fMRI), we explored whether hippocampal activity is modulated by increasing recollection confidence, increasing amount of recalled information, or both. We also investigated whether any hippocampal differences between recollection and familiarity relate to processing differences or amount of information in memory. Across two fMRI tasks, we separately compared brain responses to levels of confidence for cued word recall and word familiarity, respectively. Contrary to previous beliefs, increasing confidence/accuracy of cued recall of studied words did not increase hippocampal activity, when unconfounded by amount recollected. In contrast, additional recollection (i.e., recollecting more information than the word alone) increased hippocampal activity, although its accuracy matched that of word recall alone. Unlike cued word recall, increasing word familiarity accuracy did increase hippocampal activity linearly, although at an uncorrected level. This finding occurred although cued word recall and familiarity memory seemed matched with respect to information in memory. The detailed characteristics of these effects do not prove that word familiarity is exceptional in having hippocampal neural correlates. They suggest instead that participants fail to identify some aspects of recollection, misreporting it as familiarity, a problem with word-like items that have strong and recallable semantic associates.

Beneficial and detrimental effects of schema incongruence on memory for contextual events.

Mental schemas provide a framework into which new information can easily be integrated. In a series of experiments, we examined how incongruence that stems from a prediction error modulates memory for multicomponent events that instantiated preexisting schemas as noted in a previous study. Each event consisted of four stimulus pairs with overlapping components, presented in four blocks (A-B, B-C, C-D, D-A). A-B pairs elicited contextual expectations (A: Farm, B: Tractor) that were either met by a congruent C component (C: Farmer) or violated by an incongruent one (C: Lawyer). The baseline condition included unrelated pairs, where the C component was neither congruent nor incongruent. In experiment 2, events were presented in successive trials instead of blocks, and eye movements were recorded to analyze allocation of attention. Memory was tested through old-new item recognition followed by cued recall. Across experiments, recognition and recall performance for incongruent components was reduced compared to congruent components. Incongruent items were in some cases more accurately retrieved compared to unrelated ones, depending on task demands. Additionally, better recall was observed in the incongruent D-A pairs, compared to congruent and unrelated ones, because of reduced interference from C components. Eye-tracking revealed an increased number of fixations on C components in the incongruent and unrelated conditions. These results suggest that the integration of incongruent items into an episode is impaired, compared to congruent items, despite the contextual surprise and increased attention they elicited at encoding. However, there was a beneficial effect of prediction error on memory performance, compared to a baseline, depending on the task used.

Expectation affects learning and modulates memory experience at retrieval.

Our ability to make predictions and monitor regularities has a profound impact on the way we perceive the environment, but the effect this mechanism has on memory is not well understood. In four experiments, we explored the effects on memory of the expectation status of information at encoding or at retrieval. In a rule-learning task participants learned a contingency relationship between 6 different symbols and the type of stimulus that followed each one. Either at encoding (Experiments 1a and 1b) or at retrieval (Experiments 2a and 2b), the established relationship was violated for a subset of stimuli resulting in the presentation of both expected and unexpected stimuli. The expectation status of the stimuli was found to have opposite effects on familiarity and recollection performance, the two kinds of memory that support recognition memory. At encoding (Experiments 1a and 1b), the presentation of expected stimuli selectively enhanced subsequent familiarity performance, while unexpected stimuli selectively enhanced subsequent recollection. Similarly, at retrieval (Experiments 2a and 2b), expected stimuli were more likely to be deemed familiar than unexpected stimuli, whereas unexpected stimuli were more likely to be recollected than were expected stimuli. These findings suggest that two separate memory enhancement mechanisms exist; one sensitive and modulating the accuracy of memory for the contextually distinctive or unexpected, and the other sensitive to and modulating the accuracy of memory for the expected. Therefore, the degree to which information fits with expectation has critical implications for the type of computational mechanism that will be engaged to support memory.

Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA).

Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = - 2.12, p = .055), GABA/Glx ratio (t(12) = - 2.78, p = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%, p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome. Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network. Trial registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu).

How do memory systems detect and respond to novelty?

The efficiency of the memory system lies not only in its readiness to detect and retrieve old stimuli but also in its ability to detect and integrate novel information. In this review, we discuss recent evidence suggesting that the neural substrates sensitive to detecting familiarity and novelty are not entirely overlapping. Instead, these partially distinct familiarity and novelty signals are integrated to support recognition memory decisions. We propose here that the mediodorsal thalamus is critical for familiarity detection, and for combining novelty signals from the medial temporal lobe cortex with the relative familiarity outputs of computations performed in other cortical structures, especially the prefrontal cortex. Importantly, we argue that the anterior hippocampus has a prominent role in detecting novelty and in communicating this with midbrain and striatal structures. We argue that different types of novelty (absolute or contextual) engage different neurotransmitter systems that converge in the hippocampus. We suggest that contextual or unexpected novelty triggers dopaminergic hippocampal-midbrain coupling and noradrenergic-mediated pupil dilation. In contrast, absolute novelty triggers cholinergic-mediated hippocampal encoding accompanied by diminished pupil dilation. These two, distinct hippocampal encoding mechanisms both lead to later recollection but are sensitive to different types of novelty. We conclude that this neurotransmitter-mediated hippocampal encoding establishes the hippocampus in an encoding mode that briefly prevents the engagement of retrieval.