Pattern Separation Performance Research Articles

Robust and consistent measures of pattern separation based on information theory and demonstrated in the dentate gyrus.

Pattern separation is a valuable computational function performed by neuronal circuits, such as the dentate gyrus, where dissimilarity between inputs is increased, reducing noise and increasing the storage capacity of downstream networks. Pattern separation is studied from both in vivo experimental and computational perspectives and, a number of different measures (such as orthogonalisation, decorrelation, or spike train distance) have been applied to quantify the process of pattern separation. However, these are known to give conclusions that can differ qualitatively depending on the choice of measure and the parameters used to calculate it. We here demonstrate that arbitrarily increasing sparsity, a noticeable feature of dentate granule cell firing and one that is believed to be key to pattern separation, typically leads to improved classical measures for pattern separation even, inappropriately, up to the point where almost all information about the inputs is lost. Standard measures therefore both cannot differentiate between pattern separation and pattern destruction, and give results that may depend on arbitrary parameter choices. We propose that techniques from information theory, in particular mutual information, transfer entropy, and redundancy, should be applied to penalise the potential for lost information (often due to increased sparsity) that is neglected by existing measures. We compare five commonly-used measures of pattern separation with three novel techniques based on information theory, showing that the latter can be applied in a principled way and provide a robust and reliable measure for comparing the pattern separation performance of different neurons and networks. We demonstrate our new measures on detailed compartmental models of individual dentate granule cells and a dentate microcircuit, and show how structural changes associated with epilepsy affect pattern separation performance. We also demonstrate how our measures of pattern separation can predict pattern completion accuracy. Overall, our measures solve a widely acknowledged problem in assessing the pattern separation of neural circuits such as the dentate gyrus, as well as the cerebellum and mushroom body. Finally we provide a publicly available toolbox allowing for easy analysis of pattern separation in spike train ensembles.

88 Light and Vigorous Bouts of Acute Aerobic Exercise Positively Impact Sustained Attention and Inhibition but not Pattern Separation in Young Adults

Objective:The current study had two primary objectives: 1) To assess the dose-response relationship between acute bouts of aerobic exercise intensity and performance in multiple cognitive domains (episodic memory, attention, and executive function) and 2) To replicate and extend the literature by examining the dose-response relationship between aerobic exercise intensity and pattern separation.Participants and Methods:18 young adults (mean age = 21.6, sd = 2.6; mean education = 13.9, sd = 3.4; 50% female) were recruited from The Ohio State University and surrounding area (Columbus, OH). Participants completed control (no exercise), light intensity, and vigorous intensity exercise conditions across three counterbalanced appointments. For each participant, all three appointments occurred at approximately the same time of day with at least 2 days between appointments. Following the rest or exercise conditions and after an approximately 7 minute delay, participants completed a Mnemonic Similarity Task (MST; Stark et al., 2019) to assess pattern separation. This task was always administered first as we attempted to replicate previous studies and further clarify the relationship between acute bouts of aerobic exercise and pattern separation by implementing an exercise stimulus that varied in intensity. After the MST, three brief cognitive tasks (roughly 5 min each) were administered in a counterbalanced order: a gradual-onset continuous performance task (gradCPT; Esterman et al., 2013), the flanker task from the NIH toolbox, and a face-name episodic memory task. Here we report results from the gradCPT, which assesses sustained attention and inhibitory control. Heart rate and ratings of perceived exertion were collected to validate the rest and exercise conditions. Repeated-measures ANOVAs were used to assess the relationship between exercise condition and dependent measures of sustained attention and inhibitory control and pattern separation.Results:One-way repeated-measures ANOVAs revealed a main effect of exercise condition on gradCPT task performance for task discrimination ability (d') and commission error rate (p’s < .05). Pairwise comparisons revealed task discrimination ability was significantly higher following the light intensity exercise condition versus the control condition. Commission error rate was significantly lower for both the light and vigorous exercise conditions compared to the control condition. For the MST, two-way repeated-measures ANOVAs revealed an expected significant main effect of lure similarity on task performance; however, there was not a significant main effect of exercise intensity on task performance (or a significant interaction).Conclusions:The current study indicated that acute bouts of exercise improve both sustained attention and inhibitory control as measured with the gradCPT. We did not replicate previous work reporting that acute bouts of exercise improve pattern separation in young adults. Our results further indicate that vigorous exercise did not detrimentally impact or improve pattern separation performance. Our results indicate that light intensity exercise is sufficient to enhance sustained attention and inhibitory control, as there were no significant differences in performance following light versus vigorous exercise.

High estradiol reduces adult neurogenesis but strengthens functional connectivity within the hippocampus during spatial pattern separation in adult female rats

Adult neurogenesis in the dentate gyrus plays an important role for pattern separation, the process of separating similar inputs and forming distinct neural representations. Estradiol modulates neurogenesis and hippocampus function, but to date no examination of estradiol's effects on pattern separation have been conducted. Here, we examined estrogenic regulation of adult neurogenesis and functional connectivity in the hippocampus after the spatial pattern separation task in female rats. Ovariectomized Sprague-Dawley rats received daily injections of vehicle, 0.32 μg (Low) or 5 μg (High) of estradiol benzoate until the end of experiment. A single bromodeoxyuridine (BrdU) was injected one day after initiation of hormone or vehicle treatment and rats were tested in the delayed nonmatching to position spatial pattern separation task in the 8-arm radial maze for 12 days beginning two weeks after BrdU injection. Rats were perfused 90 min after the final trial and brain sections were immunohistochemically stained for BrdU/neuronal nuclei (NeuN) (new neurons), Ki67 (cell proliferation), and the immediate early gene, zif268 (activation). Results showed that high, but not low, estradiol reduced the density of BrdU/NeuN-ir cells and had significant inter-regional correlations of zif268-ir cell density in the hippocampus following pattern separation. Estradiol treatment did not influence pattern separation performance or strategy use. These results show that higher doses of estradiol can reduce neurogenesis but at the same time increases correlations of activity of neurons within the hippocampus during spatial pattern separation.

Conditioned place avoidance is associated with a distinct hippocampal phenotype, partly preserved pattern separation, and reduced reactive oxygen species production after stress.

Stress is associated with contextual memory deficits, which may mediate avoidance of trauma-associated contexts in posttraumatic stress disorder. These deficits may emerge from impaired pattern separation, the independent representation of similar experiences by the dentate gyrus-Cornu Ammonis 3 (DG-CA3) circuit of the dorsal hippocampus, which allows for appropriate behavioral responses to specific environmental stimuli. Neurogenesis in the DG is controlled by mitochondrial reactive oxygen species (ROS) production, and may contribute to pattern separation. In Experiment 1, we performed RNA sequencing of the dorsal hippocampus 16 days after stress in rats that either develop conditioned place avoidance to a predator urine-associated context (Avoiders), or do not (Non-Avoiders). Weighted genome correlational network analysis showed that increased expression of oxidative phosphorylation-associated gene transcripts and decreased expression of gene transcripts for axon guidance and insulin signaling were associated with avoidance behavior. Based on these data, in Experiment 2, we hypothesized that Avoiders would exhibit elevated hippocampal (HPC) ROS production and degraded object pattern separation (OPS) compared with Nonavoiders. Stress impaired pattern separation performance in Non-Avoider and Avoider rats compared with nonstressed Controls, but surprisingly, Avoiders exhibited partly preserved pattern separation performance and significantly lower ROS production compared with Non-Avoiders. Lower ROS production was associated with better OPS performance in Stressed rats, but ROS production was not associated with OPS performance in Controls. These results suggest a strong negative association between HPC ROS production and pattern separation after stress, and that stress effects on these outcome variables may be associated with avoidance of a stress-paired context.

APOE Genotype Moderates the Relationship Between Plasma Phosphorylated‐tau181 and Pattern Separation Performance in Non‐demented Adults

AbstractBackgroundThe apolioprotein e (APOE) e4 allele enhances risk for Alzheimer’s disease (AD), particularly an amnestic AD phenotype with medial temporal lobe tau pathology. Pattern separation, the ability to discern novel yet similar information from previously learned information, is a cognitive marker of hippocampal function. APOE e4 carriers often exhibit pattern separation deficits prior to conversion to AD dementia, however the impact of APOE on tau‐related pattern separation performance is unknown. We examined the relationship between plasma P‐tau181 and pattern separation performance in non‐demented adults, and tested whether this association was dependent on APOE e4 genotype.MethodsPlasma P‐tau181 levels were measured (Quanterix Simoa) in 171 non‐demented adults (139 cognitively unimpaired, 32 mild cognitive impairment; 29% APOE e4+, 54% female, aged 52‐92) who completed a validated behavioral task of visual pattern separation recognition. The lure discrimination index (LDI), reflecting ability to discriminate similar ‘lure’ items from old items, was modeled as the primary outcome. Linear regression examined LDI scores as a function of plasma P‐tau181, APOE4 genotype, and their interaction, controlling for age, sex, and education.ResultAPOE e4+ had higher plasma P‐tau181 than e4‐ (Cohen’s d=0.64, p<0.001), but APOE4 groups did not differ on LDI scores (Cohen’s d=0.27, p=0.124). In the full sample, higher plasma P‐tau181 significantly related to lower (worse) LDI scores (β=‐0.17, p=0.028). APOE4 status significantly moderated the relationship between plasma P‐tau181 and LDI scores (β=‐0.29, p=0.030) such that higher P‐tau181 related to lower LDI scores in e4+ (β=‐0.38, p=0.004) but not in e4‐ individuals (β=‐0.02, p=0.824).ConclusionsAPOE e4+ individuals had elevated plasma P‐tau181, which in turn related to worse pattern separation performance only within e4+ individuals. These data suggest that APOE4‐related elevations in plasma P‐tau181 may be particularly sensitive to hippocampal functioning outcomes prior to frank dementia, which could reflect underlying hippocampal hyperexcitability due to e4‐mediated GABAergic interneuron loss. Future work incorporating imaging markers of brain structure and function may help elucidate whether P‐tau181‐related alterations in pattern separation among e4+ individuals are mediated by hippocampal‐specific mechanisms.

An emergent temporal basis set robustly supports cerebellar time-series learning.

The cerebellum is considered a "learning machine" essential for time interval estimation underlying motor coordination and other behaviors. Theoretical work has proposed that the cerebellum's input recipient structure, the granule cell layer (GCL), performs pattern separation of inputs that facilitates learning in Purkinje cells (P-cells). However, the relationship between input reformatting and learning has remained debated, with roles emphasized for pattern separation features from sparsification to decorrelation. We took a novel approach by training a minimalist model of the cerebellar cortex to learn complex time-series data from time-varying inputs, typical during movements. The model robustly produced temporal basis sets from these inputs, and the resultant GCL output supported better learning of temporally complex target functions than mossy fibers alone. Learning was optimized at intermediate threshold levels, supporting relatively dense granule cell activity, yet the key statistical features in GCL population activity that drove learning differed from those seen previously for classification tasks. These findings advance testable hypotheses for mechanisms of temporal basis set formation and predict that moderately dense population activity optimizes learning.NEW & NOTEWORTHY During movement, mossy fiber inputs to the cerebellum relay time-varying information with strong intrinsic relationships to ongoing movement. Are such mossy fibers signals sufficient to support Purkinje signals and learning? In a model, we show how the GCL greatly improves Purkinje learning of complex, temporally dynamic signals relative to mossy fibers alone. Learning-optimized GCL population activity was moderately dense, which retained intrinsic input variance while also performing pattern separation.

Moderate effect of early-life experience on dentate gyrus function

The development, maturation, and plasticity of neural circuits are strongly influenced by experience and the interaction of an individual with their environment can have a long-lasting effect on cognitive function. Using an enriched environment (EE) paradigm, we have recently demonstrated that enhancing social, physical, and sensory activity during the pre-weaning time in mice led to an increase of inhibitory and excitatory synapses in the dentate gyrus (DG) of the hippocampus. The structural plasticity induced by experience may affect information processing in the circuit. The DG performs pattern separation, a computation that enables the encoding of very similar and overlapping inputs into dissimilar outputs. In the presented study, we have tested the hypothesis that an EE in juvenile mice will affect DG’s functions that are relevant for pattern separation: the decorrelation of the inputs from the entorhinal cortex (EC) and the recruitment of the principal excitatory granule cell (GC) during behavior. First, using a novel slice electrophysiology protocol, we found that the transformation of the incoming signal from the EC afferents by individual GC is moderately affected by EE. We further show that EE does not affect behaviorally induced recruitment of principal excitatory GC. Lastly, using the novel object recognition task, a hippocampus-dependent memory test, we show that the ontogeny of this discrimination task was similar among the EE mice and the controls. Taken together, our work demonstrates that pre-weaning enrichment moderately affects DG function.

Effects Of Acute Aerobic Exercise On Behavioral Pattern Separation Performance In Older Adults

PURPOSE: Ample evidence suggests moderate-intensity aerobic exercise is beneficial for hippocampal structure and function. Furthermore, recent studies in younger adults suggest a single session of aerobic exercise provides immediate benefits to behavioral pattern separation performance, a highly hippocampal-specific memory task. However, no work has explored how a single session of aerobic exercise might alter pattern separation performance in older adults, who generally exhibit deficits in pattern separation performance and hippocampal deterioration in relation to younger adults. METHODS: To address this question, we conducted a within-subject acute exercise study in 31 cognitively healthy and physically active older adults (70.1 (±6.1) years). Participants performed baseline testing and then completed two experimental day visits in counterbalanced order. On the experimental days, they performed different iterations of a behavioral pattern separation task on the computer before and after 30 minutes of moderate intensity aerobic exercise on a cycle ergometer or 30 minutes of quiet seated rest. Linear mixed-effects model analysis was employed in which condition order was controlled for, time (pre vs. post) and condition (exercise vs. rest) were modeled as fixed effects, and subject was modeled as a random effect. RESULTS: No significant time by condition interaction effect was found for general object recognition (F(1,31) = 1.25, p = .267, η2 = .01) and a positive, but non-significant interaction effect was found for pattern separation performance following the exercise condition (F(1,31) = 3.56, p = .062, η2 = .04). Furthermore, a post-intervention only analysis indicated that there was no significant difference between the exercise and rest condition for general object recognition (F(1,31) = 1.46, p = .236, η2 = .05), but that participants performed significantly better on the pattern separation task (F(1,31) = 8.86, p = .006, η2 = .22) following the exercise condition. CONCLUSIONS: Our results suggest a single session of moderate-intensity aerobic exercise may lead to reduced interference and better pattern separation performance in healthy older adults, suggesting immediate benefits for hippocampal-specific memory function.

Monocyte Polarization As A Biomarker Of Cardiorespiratory And Cognitive Health In Active Older Adults: A Pilot Study.

The aging process is characterized by a chronic, low-grade pro-inflammatory state that may contribute to age-related conditions such as Alzheimer’s Disease (AD). Recent frameworks suggest monocyte phenotypes play key roles in the aging immune response that may exacerbate AD pathology and contribute to cognitive decline. Lifestyle behaviors, such as aerobic exercise training, can be neuroprotective and immunoprotective but the relationships between monocyte phenotypes, cardiorespiratory fitness, and cognitive function are poorly understood.PURPOSE:To explore the associations between monocyte phenotypes, cardiorespiratory fitness (VO2max), and performance in a hippocampal-dependent pattern separation task. METHODS:Active older adults (70 ± 6.7y, n = 24) were recruited for this study. Baseline VO2max was obtained via graded exercise test and pattern separation performance with a previously validated computerized test. Following a 12 h fast, Peripheral blood mononuclear cells (PBMCs) were isolated via Ficoll-gradient and immunostained with cell surface markers CD14 and CD16 to sort monocytes via flow cytometry. Spearman’s rank-order correlations (rs) were employed to determine the associations between monocyte phenotypes, VO2max, and cognitive outcomes. A multiple linear regression analysis was used to determine the association between monocyte polarization and outcomes of interest. RESULTS:No significant associations were found between classical (rs = -0.09, p > .05), intermediate (rs = 0.18, p > .05), or non-classical (rs = 0.10, p > .05) monocytes and pattern separation performance. Classical monocytes showed a direct correlation with VO2max (rs = 0.26, p = .01) while intermediate (rs = -0.18, p = .01) and non-classical (rs = -0.24, p = .01) monocytes showed inverse correlations with VO2max. A multiple regression model predicting VO2max from all monocyte phenotypes, controlling for age and sex, was significant (F(5,18) = 9.38, p = <.001, R2 = 0.64); follow-up contrasts indicated only intermediate monocytes were a significant predictor of VO2max (t(18) = -2.25, p = 0.03).CONCLUSIONS:Our results suggest pro-inflammatory monocyte phenotypes may negatively relate to VO2max in active older adults, but monocyte phenotypes did not relate to cognitive outcomes.

Disynaptic effect of hilar cells on pattern separation in a spiking neural network of hippocampal dentate gyrus.

We study the disynaptic effect of the hilar cells on pattern separation in a spiking neural network of the hippocampal dentate gyrus (DG). The principal granule cells (GCs) in the DG perform pattern separation, transforming similar input patterns into less-similar output patterns. In our DG network, the hilus consists of excitatory mossy cells (MCs) and inhibitory HIPP (hilar perforant path-associated) cells. Here, we consider the disynaptic effects of the MCs and the HIPP cells on the GCs, mediated by the inhibitory basket cells (BCs) in the granular layer; MC BC GC and HIPP BC GC. The MCs provide disynaptic inhibitory input (mediated by the intermediate BCs) to the GCs, which decreases the firing activity of the GCs. On the other hand, the HIPP cells disinhibit the intermediate BCs, which leads to increasing the firing activity of the GCs. In this way, the disynaptic effects of the MCs and the HIPP cells are opposite. We investigate change in the pattern separation efficacy by varying the synaptic strength [from the pre-synaptic X (= MC or HIPP) to the post-synaptic BC]. Thus, sparsity for the firing activity of the GCs is found to improve the efficacy of pattern separation, and hence the disynaptic effects of the MCs and the HIPP cells on the pattern separation become opposite ones. In the combined case when simultaneously changing both and , as a result of balance between the two competing disynaptic effects of the MCs and the HIPP cells, the efficacy of pattern separation is found to become the highest at their original default values where the activation degree of the GCs is the lowest. We also note that, while the GCs perform pattern separation, sparsely synchronized rhythm is found to appear in the population of the GCs. Hence, we examine quantitative association between population and individual firing behaviors in the sparsely synchronized rhythm and pattern separation. They are found to be strongly correlated. Consequently, the better the population and individual firing behaviors in the sparsely synchronized rhythm are, the more pattern separation efficacy becomes enhanced.

Biased 5-HT1A receptor agonists F13714 and NLX-101 differentially affect pattern separation and neuronal plasticity in rats after acute and chronic treatment

Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.

Monthly computerized at‐home assessments to detect cognitive change in preclinical Alzheimer’s disease

AbstractBackgroundAlongside the increased focus on detecting Alzheimer’s disease (AD) pathology in the preclinical stage, there is a need to more rapidly track AD‐related cognitive changes that may emerge during this stage. Computerized cognitive testing has the potential to achieve this by enabling more frequent, remote, unsupervised assessments. Here, we aimed to investigate whether monthly at‐home assessments of a modified version of the Behavioural Pattern Separation Task‐Object Version (BPSO) could detect cognitive change in cognitively unimpaired (CU) individuals with and without abnormal AD biomarkers.MethodN=110 CU participants (age=77.1±4.9, 61% female, MMSE 29±1.3) from the Harvard Aging Brain Study completed the BPSO monthly at‐home on an iPad as part of the Cogstate C3 battery for up to one year (6.3±3.9 months follow‐up). All participants underwent PIB‐PET imaging (1.25±1.05 years before at‐home baseline) and a subset (n=82) underwent Flortaucipir PET (0.56±0.4 years before at‐home baseline). Primary outcome of the BPSO is a metric reflecting the ability to correctly discriminate between stimuli that are similar but not identical to previously learned targets (score range 0‐1, higher scores reflecting better performance). Linear mixed models were used to characterize BPSO performance over months (including both linear and quadratic time terms to investigate nonlinear change), and to examine associations with amyloid (dichotomous) and medial‐temporal tau deposition (continuous) while adjusting for age, sex, education and their interactions with time.ResultOverall, individuals’ BPSO performance improved over months, as shown by a significant quadratic effect of time (β=‐.002,p&lt;.001) with a plateauing learning curve (Figure 1). On average, amyloid‐positive individuals (n=29) showed slightly worse BPSO performance (β=‐.06,p=.03) than amyloid‐negative individuals, but similar trajectories over time. However, the baseline amyloid effect was attenuated when limiting the sample to those with both amyloid and tau imaging. Less improvement over the year was associated with greater tau burden in the entorhinal cortex (Time*tau β=‐0.02,p=.019) (Figure 2).ConclusionWe show that subtle alterations in pattern separation performance over repeated exposure in CU individuals are associated with tau deposition in the medial‐temporal lobe. This implies that unsupervised computerized testing using monthly learning paradigms may be an efficient way to early detect cognitive change associated with preclinical AD.

Spatial Pattern Separation Testing Differentiates Alzheimer's Disease Biomarker-Positive and Biomarker-Negative Older Adults With Amnestic Mild Cognitive Impairment.

Background: The hippocampus, entorhinal cortex (EC), and basal forebrain (BF) are among the earliest regions affected by Alzheimer’s disease (AD) pathology. They play an essential role in spatial pattern separation, a process critical for accurate discrimination between similar locations.Objective: We examined differences in spatial pattern separation performance between older adults with amnestic mild cognitive impairment (aMCI) with AD versus those with non-Alzheimer’s pathologic change (non-AD) and interrelations between volumes of the hippocampal, EC subregions and BF nuclei projecting to these subregions (medial septal nuclei and vertical limb of the diagonal band of Broca – Ch1-2 nuclei) with respect to performance.Methods: Hundred and eighteen older adults were recruited from the Czech Brain Aging Study. Participants with AD aMCI (n = 37), non-AD aMCI (n = 26), mild AD dementia (n = 26), and cognitively normal older adults (CN; n = 29) underwent spatial pattern separation testing, cognitive assessment and brain magnetic resonance imaging.Results: The AD aMCI group had less accurate spatial pattern separation performance than the non-AD aMCI (p = 0.039) and CN (p < 0.001) groups. The AD aMCI and non-AD groups did not differ in other cognitive tests. Decreased BF Ch1-2 volume was indirectly associated with worse performance through reduced hippocampal tail volume and reduced posteromedial EC and hippocampal tail or body volumes operating in serial.Conclusion: The study demonstrates that spatial pattern separation testing differentiates AD biomarker positive and negative older adults with aMCI and provides evidence that BF Ch1-2 nuclei influence spatial pattern separation through the posteromedial EC and the posterior hippocampus.

Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggest Dentate Gyrus Pathology Linked to NMDA Receptor Hypofunction

BackgroundConverging evidence from neuroimaging and postmortem studies suggests that hippocampal subfields are differentially affected in schizophrenia. Recent studies report dentate gyrus dysfunction in chronic schizophrenia, but the underlying mechanisms remain to be elucidated. Here, we sought to examine if this deficit is already present in first-episode psychosis and if NMDA receptor hypofunction, a putative central pathophysiological mechanism in schizophrenia, experimentally induced by ketamine, would result in a similar abnormality. MethodsWe applied a mnemonic discrimination task selectively taxing pattern separation in two experiments: 1) a group of 23 patients with first-episode psychosis and 23 matched healthy volunteers and 2) a group of 19 healthy volunteers before and during a ketamine challenge (0.27 mg/kg over 10 min, then 0.25 mg/kg/hour for 50 min, 0.01 mL/s). We calculated response bias–corrected pattern separation and recognition scores. We also examined the relationships between task performance and symptom severity as well as ketamine levels. ResultsWe reported a deficit in pattern separation performance in patients with first-episode psychosis compared with healthy volunteers (p = .04) and in volunteers during the ketamine challenge compared with baseline (p = .003). Pattern recognition was lower in patients with first-episode psychosis than in control subjects (p < .01). Exploratory analyses revealed no correlation between task performance and Repeatable Battery for the Assessment of Neuropsychological Status total scores or positive symptoms in patients with first-episode psychosis or with ketamine serum levels. ConclusionsWe observed a mnemonic discrimination deficit in both datasets. Our findings suggest a tentative mechanistic link between dentate gyrus dysfunction in first-episode psychosis and NMDA receptor hypofunction.

Lower pattern recognition memory scores in anorexia nervosa

BackgroundThere is extensive evidence for volumetric reductions in the hippocampus in patients with anorexia nervosa (AN), however the impact on function is unclear. Pattern separation and recognition are hippocampus-dependent forms of learning thought to underlie stimulus discrimination.MethodsThe present study used the Mnemonic Similarity Task to investigate pattern separation and recognition for the first time in patients with AN (N = 46) and healthy controls (N = 56). An Analysis of Covariance examined between-group differences, controlling for age, antidepressant use and method of task delivery (remote vs. in person).ResultsWhen controlling for covariates, pattern recognition memory scores were lower in the AN group with a medium effect size (d = 0.51). In contrast, there was a small effect whereby patients with AN had a greater pattern separation score than controls (d = 0.34), albeit this difference was not significant at the p = 0.05 threshold (p = 0.133). Furthermore, pattern separation and recognition memory abilities were not related to age, body mass index, eating disorder psychopathology or trait anxiety levels.ConclusionsThis preliminary study provides initial evidence for an imbalance in pattern separation and recognition abilities in AN, a hippocampus-dependent cognitive ability. Further studies should endeavour to investigate pattern separation and recognition performance further in AN, as well as investigate other hippocampus-dependent functions.

APOE moderates the effect of hippocampal blood flow on memory pattern separation in clinically normal older adults.

Pattern separation, the ability to differentiate new information from previously experienced similar information, is highly sensitive to hippocampal structure and function and declines with age. Functional MRI studies have demonstrated hippocampal hyperactivation in older adults compared to young, with greater task-related activation associated with worse pattern separation performance. The current study was designed to determine whether pattern separation was sensitive to differences in task-free hippocampal cerebral blood flow (CBF) in 130 functionally intact older adults. Given prior evidence that apolipoprotein E e4 (APOE e4) status moderates the relationship between CBF and episodic memory, we predicted a stronger negative relationship between hippocampal CBF and pattern separation in APOE e4 carriers. An interaction between APOE group and right hippocampal CBF was present, such that greater right hippocampal CBF was related to better lure discrimination in noncarriers, whereas the effect reversed directionality in e4 carriers. These findings suggest that neurovascular changes in the medial temporal lobe may underlie memory deficits in cognitively normal older adults who are APOE e4 carriers.

Neurocognitive mechanisms of spatial pattern separation in older adults with and without subclinical memory impairment

AbstractBackgroundDecline in episodic memory is a hallmark feature of Alzheimer’s disease (AD). Episodic memories can be operationalized as detailed conjunctions of items and their spatiotemporal context. Our past work has uncovered deficits in pattern separation of similar object memories in nondemented older adults. However, separation of similar spatial locations was only slightly impaired in this population. We hypothesized that these deficits may be more readily observable in individuals with subclinical memory impairment (assessed by verbal list recall). We also sought to determine the neural mechanisms by which spatial pattern separation deficits may manifest in older adults, focusing on the posterior parietal network which is involved in spatial processing and implicated in AD.MethodsTwo cohorts were included in this analysis. The first is a group of older adults with subclinical memory impairment (aged impaired – AI, age range: 61‐91; mean MMSE: 28.3 ± 1.50; mean RAVLT delayed recall: 9.66 ± 4.05). The second is a group of non‐demented older adults without memory impairment (aged unimpaired – AU; age range: 61‐86; mean MMSE: 28.1 ± 1.59; RAVLT delayed recall: 11.4 ± 3.01). Participants underwent whole brain high‐resolution resting state functional magnetic resonance imaging (1.5 x 1.5 x 2 mm resolution). They were also administered a battery of neuropsychological tests including tests of object and spatial pattern separation. We used performance on the RAVLT as the outcome predicted by performance on the discrimination tests. Specifically, we used delayed recall (DR), retroactive interference (RI), and percent forgetting (PF).ResultsBehaviorally, spatial, but not item, pattern separation performance predicted RAVLT DR, RI and PF scores in the AI group, but not the AU group. Functional connectivity analyses revealed that the connectivity of regions involved in spatial processing was significantly related to spatial pattern separation performance in the AI group, but not the AU group.ConclusionThese results validate the neurobiological basis of spatial pattern separation and suggest that such tasks can be used to detect early stages of AD, which has important implications for future diagnostics and treatment approaches.

Spatial Pattern Separation in Early Alzheimer's Disease.

The hippocampus, entorhinal cortex, and basal forebrain are among the first brain structures affected by Alzheimer's disease (AD). They play an essential role in spatial pattern separation, a process critical for accurate encoding of similar spatial information. Our aim was to examine spatial pattern separation and its association with volumetric changes of the hippocampus, entorhinal cortex, and basal forebrain nuclei projecting to the hippocampus (the medial septal nuclei and vertical limb of the diagonal band of Broca - Ch1-2 nuclei) in the biomarker-defined early clinical stages of AD. A total of 98 older adults were recruited from the Czech Brain Aging Study cohort. The participants with amnestic mild cognitive impairment (aMCI) due to AD (n = 44), mild AD dementia (n = 31), and cognitively normal older adults (CN; n = 23) underwent spatial pattern separation testing, comprehensive cognitive assessment, and MRI brain volumetry. Spatial pattern separation accuracy was lower in the early clinical stages of AD compared to the CN group (p < 0.001) and decreased with disease severity (CN > aMCI due to AD > AD dementia). Controlling for general memory and cognitive performance, demographic characteristics and psychological factors did not change the results. Hippocampal and Ch1-2 volumes were directly associated with spatial pattern separation performance while the entorhinal cortex operated on pattern separation indirectly through the hippocampus. Smaller volumes of the hippocampus, entorhinal cortex, and basal forebrain Ch1-2 nuclei are linked to spatial pattern separation impairment in biomarker-defined early clinical AD and may contribute to AD-related spatial memory deficits.

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.

Phosphodiesterase inhibitors roflumilast and vardenafil prevent sleep deprivation-induced deficits in spatial pattern separation.

Sleep deprivation (SD) is known to impair hippocampus‐dependent memory processes, in part by stimulating the phosphodiesterase (PDE) activity. In the present study, we assessed in mice whether SD also affects spatial pattern separation, a cognitive process that specifically requires the dentate gyrus (DG) subregion of the hippocampus. Adult male mice were trained in an object pattern separation (OPS) task in the middle of the light phase and then tested 24 hr thereafter. In total, we conducted three studies using the OPS task. In the first study, we validated the occurrence of pattern separation and tested the effects of SD. We found that 6 hr of SD during the first half of the light phase directly preceding the test trial impaired the spatial pattern separation performance. As a next step, we assessed in two consecutive studies whether the observed SD‐induced performance deficits could be prevented by the systemic application of two different PDE inhibitors that are approved for human use. Both the PDE4 inhibitor roflumilast and PDE5 inhibitor vardenafil successfully prevented SD‐induced deficits in spatial pattern separation. As a result, these PDE inhibitors have clinical potential for the prevention of memory deficits associated with loss of sleep.