A task to assess behavioral pattern separation (BPS) in humans: Data from healthy aging and mild cognitive impairment

It is known that intergenerational inheritance can be induced by environmental changes in parents. These studies usually focus on negative stressors that affect the offspring adversely. There is increasing evidence that exercise improves learning and memory in humans and mice. These beneficial effects could be mediated by enhanced hippocampal neurogenesis. Whether these effects could be inherited by future generations remains to be seen. This study analysed if paternal exercise training could facilitate hippocampal‐dependent novel object recognition memory and pattern separation performance in offspring. Firstly, male progenitors were subjected to a forced moderate exercise protocol for eight weeks before mating. All male experimental animals underwent the following behavioural protocols: an activity cage and two different protocols of a novel object recognition memory test and a pattern separation test, both protocols differing in the level of difficulty. Regarding basal motor activity, no differences were found between experimental groups in a known environment. As for the novel object recognition and pattern separation tests, only male progenitors that had undergone the exercise protocol were able to discriminate the novel object and the change of pattern in the difficult protocols. No significant differences were found in postnatal behaviour. However, the behavioural outcomes in adulthood showed that only the offspring of male progenitors that had undergone physical exercise displayed facilitation in novel object recognition memory and pattern separation performance. In order to assess adult hippocampal neurogenesis, immunohistochemistry against different neurogenesis markers was performed. Furthermore, whole‐genome sequence analyses showed differential gene expression among experimental groups. These results suggest that beneficial effects of exercise training on learning and memory can be inherited.Support or Funding InformationWork was supported by project grants from Spanish Ministry of Economy and Competitiveness BFU2013‐48907‐R and BFU2016‐77162‐R (to J.L.T.). A.F. was funded by a JaE‐DOC CSIC grant, I.L.T. was funded by an FPI grant, and K.R.McG. was funded by a contract associated with the project grants above mentioned (to J.L.T.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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.

Replay of hippocampal neural representations during sleep is thought to promote systems consolidation of declarative memory. How this reprocessing of memory during sleep affects the hippocampal representation itself, is unclear. Here we tested hippocampal stimulus processing (i.e., pattern separation) before and after periods of sleep and wakefulness in humans (female and male participants). Pattern separation deteriorated across the wake period but remained stable across sleep (p = 0.013) with this sleep-wake difference being most pronounced for stimuli with low similarity to targets (p = 0.006). Stimuli with the highest similarity showed a reversed pattern with reduced pattern separation performance after sleep (p = 0.038). Pattern separation performance was positively correlated with sleep spindle density, slow oscillation density, and theta power phase-locked to slow oscillations. Sleep, presumably by neural memory replay, shapes hippocampal representations and enhances computations of pattern separation to subsequent presentation of similar stimuli.SIGNIFICANCE STATEMENT The consolidation of hippocampus-dependent memories is causally related to reactivation during sleep of previously encoded representations. Here, we show that reactivation-based consolidation processes during sleep shape the hippocampal representation itself. We studied the effect of sleep and wakefulness on pattern separation (i.e., orthogonalization of similar representations) and completion performance (i.e., recall of a memory in light of noisy input) that are essential cognitive elements of encoding and retrieval of information by the hippocampus. Our results demonstrate that pattern separation was stabilized after sleep but diminished after wakefulness. We further showed that pattern separation was related to EEG oscillatory parameters of non-REM sleep serving as markers of sleep-dependent memory consolidation and hippocampal reactivation.

Introduction: Schizophrenia and anxiety disorders place a great burden on the patients suffering from it and on society. The cognitive symptoms of both diseases can be caused partly by impaired pattern separation. Pattern separation is the ability to make distinct representations out of highly overlapping information. Improving pattern separation could slow down the progression of the above mentioned disorders and thus improve the quality of life of the patients. Alterations in gene expression can lead to differences in pattern separation performance. Methylation of DNA is one of the epigenetic changes controlled by DNA methyltransferases (DNMT) that can alter such gene expression levels without changing the underlying DNA sequence. In this study, the DNMT inhibitor RG108 was given to mice in order to investigate its effect on pattern separation performance. Methods: 36 male C57BL/6 mice were used. Pattern separation performance was measured using the novel Object Pattern Separation task. It consists of two trials with two identical objects. In the second trial one of the objects is replaced along a vertical axis, while the second object stays in the same position. For the assessment of pattern separation the object is replaced at increasingly distinct locations. The most suitable inter-trial interval and position were assessed and pattern separation performance was measured after an intraperitoneal injection of either saline, 0.1mg/kg RG108 or 0.3mg/kg RG108. After 48 hours mice received a saline injection and pattern separation performance was measured again to check for carry-over effects. Lastly, a 24 hour inter-trial interval was used to unravel RG108 effects on long-term memory. After the behavioral task, the mice were decapitated and the dorsal hippocampus was dissected to quantify the expression of six target genes with qPCR. Results: RG108 leads to an acute, dose-dependent increase in pattern separation. This effect vanishes after 48 hours. Furthermore, RG108 administration is not sufficient to 89 enhance pattern separation in such a way that animals can still remember the object’s location after 24 hours. Whereas BDNF4, BDNF9, GRIA1, HDAC2 and HEY1 expressions do not change after acute administration of RG108, BDNF1 expression increases and can be the underlying reason for the improvement in pattern separation. Future studies are needed to reveal the possible methylation changes and to study the effect of chronic treatment with this drug.

P203 Is more better? A protocol to investigate the (neural) effects of repeated vs. single tACS in healthy and pathological ageing

Aims: Subfields of the hippocampus have long been held responsible for the pattern separation function of episodic memory. The total neuron numbers of the entorhinal cortex (EC), which gives the major input to the hippocampus, the dentate gyrus (DG), and CA3 and their ratio to each other is thought to be important for the pattern separation process. In this study, the relationship between the volumes of the EC and hippocampal subfields and behavioral pattern separation performance was investigated. Methods: 3D brain MRI images of 39 university students were obtained and the volumes of EC and hippocampal subfields (CA1, CA2-CA3, CA4-DG) were analyzed on the volBrain online automatic brain volumetry system. All participants were evaluated with a cognitive test for pattern separation performance. Finally, the correlation between the volume of brain areas and pattern separation performance score was statistically analyzed. Results: Total and right CA2-CA3 volume had positive correlation with pattern separation score (p=0.036, p=0.028 respectively) and negative correlation with recognition fail (p=0.013, p=0.009 respectively). CA1 volume also had a negative correlation with recognition fail (p=0.040) while the ratio of EC volume to CA4-DG was positively correlated with success of pattern separation (p=0.016). Conclusion: The results contribute to our understanding of memory function by indicating the relationship between EC-to-DG divergence and CA2-CA3 volume with pattern separation.

Impaired spatial pattern separation performance in temporal lobe epilepsy is associated with visuospatial memory deficits and hippocampal volume loss

Mild cognitive impairment (MCI) may be a precursor to dementia, at least in some cases. Dementia and MCI are associated with neuropsychiatric symptoms in clinical samples. Only 2 population-based studies exist of the prevalence of these symptoms in dementia, and none exist for MCI. To estimate the prevalence of neuropsychiatric symptoms in dementia and MCI in a population-based study. Cross-sectional study derived from the Cardiovascular Health Study, a longitudinal cohort study. A total of 3608 participants were cognitively evaluated using data collected longitudinally over 10 years and additional data collected in 1999-2000 in 4 US counties. Dementia and MCI were classified using clinical criteria and adjudicated by committee review by expert neurologists and psychiatrists. A total of 824 individuals completed the Neuropsychiatric Inventory (NPI); 362 were classified as having dementia, 320 as having MCI; and 142 did not meet criteria for MCI or dementia. Prevalence of neuropsychiatric symptoms, based on ratings on the NPI in the previous month and from the onset of cognitive symptoms. Of the 682 individuals with dementia or MCI, 43% of MCI participants (n = 138) exhibited neuropsychiatric symptoms in the previous month (29% rated as clinically significant) with depression (20%), apathy (15%), and irritability (15%) being most common. Among the dementia participants, 75% (n = 270) had exhibited a neuropsychiatric symptom in the past month (62% were clinically significant); 55% (n = 199) reported 2 or more and 44% (n = 159) 3 or more disturbances in the past month. In participants with dementia, the most frequent disturbances were apathy (36%), depression (32%), and agitation/aggression (30%). Eighty percent of dementia participants (n = 233) and 50% of MCI participants (n = 139) exhibited at least 1 NPI symptom from the onset of cognitive symptoms. There were no differences in prevalence of neuropsychiatric symptoms between participants with Alzheimer-type dementia and those with other dementias, with the exception of aberrant motor behavior, which was more frequent in Alzheimer-type dementia (5.4% vs 1%; P =.02). Neuropsychiatric symptoms occur in the majority of persons with dementia over the course of the disease. These are the first population-based estimates for neuropsychiatric symptoms in MCI, indicating a high prevalence associated with this condition as well. These symptoms have serious adverse consequences and should be inquired about and treated as necessary. Study of neuropsychiatric symptoms in the context of dementia may improve our understanding of brain-behavior relationships.

BackgroundSeveral fMRI studies in patients with Mild Cognitive Impairment (MCI) found hippocampal hyperactivity during a pattern separation task, which was associated with accelerated accumulation of Alzheimer's disease pathology, faster disease progression and more pronounced cognitive decline. We tested whether real‐time fMRI neurofeedback, during which individuals learn to regulate region specific brain activity, can reduce hippocampal hyperactivity and thereby improve pattern separation performance.MethodsSeventy‐eight participants, categorized by clinical diagnosis (MCI or healthy), blood‐based biomarker (pTau181 above or below cutoff), or amyloid positivity risk (high or low), were enrolled. Participants learned how to downregulate activity in their own hippocampus or in a control region (two times, for 1 hour each). One week later, we re‐assessed hippocampal activity and pattern separation performance.ResultsDownregulation of hippocampal activity during neurofeedback led to significantly reduced hippocampal activity and significantly improved pattern separation performance one week later. Downregulation of activity in a control region had no significant effect on hippocampal activity and only minor effects on pattern separation performance. These findings were consistent across subgroups based on clinical diagnosis, amyloid positivity risk, and biomarker status.ConclusionOur results indicate that real‐time fMRI neurofeedback can effectively downregulate hippocampal activity and improve pattern separation performance in individuals at risk of developing Alzheimer's disease. This approach holds promise as a potential therapeutic tool to address hippocampal dysfunction in early Alzheimer's disease.

Subjective memory complaints are often used as diagnostic criteria for several neurocognitive disorders. Although a number of studies have examined subjective memory and its associations with memory functioning in adulthood and old age, it is still an open question whether subjective perceptions of one's memory indicate actual memory functioning or whether they are rather derived from factors other than memory, such as depressive symptoms. The studies in this special section examine subjective perceptions of memory functioning and their associations with objectively measured memory performance in general and in clinical populations. The four articles adopt cross-sectional and longitudinal methodologies and offer key insights into the nature, correlates, and developmental trajectories of subjective memory. To begin with, the studies compiled in this special section demonstrate that changes in subjective memory perceptions are indeed associated with changes in memory performance [Zimprich and Kurtz, this issue, pp. 223-231], but the size of associations between levels of and changes in subjective memory and memory performance is in part modulated by personality characteristics and depressive symptoms [Hülür et al., this issue, pp. 232-240]. Second, the studies compiled here show that factors other than memory are also closely associated with memory perceptions, including functional health as well as domain-general and health-specific control beliefs [Luszcz et al., this issue, pp. 241-250]. Third, the study by Thompson et al. [this issue, pp. 251-257] shows that self- and informant-reports of retrospective and prospective memory difficulties are not associated with performance-based measures and does not sufficiently differentiate between healthy controls and patients diagnosed with mild cognitive impairment or dementia. In our editorial, we put these findings in perspective and discuss implications for research and practice. To extend our knowledge, we conclude by outlining two key avenues for future research: (i) longitudinal multivariate studies of the construct space surrounding subjective memory and (ii) the viability of experience sampling studies with daily or hourly measurements to tackle some of the mechanisms underlying these associations.

Background/Aims Language changes are the earliest signs and symptoms of mild cognitive impairment and Alzheimer's disease. The aim of this study was to explore the language difference performance between people with mild cognitive impairment, people with Alzheimer's disease and healthy individuals as a control group. To accomplish this aim, the language profile of both mild cognitive impairment and Alzheimer's disease needs to be characterised to determine which feature is more affected by both mild cognitive impairment and Alzheimer's disease among expressive language, receptive language, executive function and memory performance. Methods This case-control prospective study involved 90 participants. The Mini-Mental Status Examination and the Functional Assessment Staging Tool were used to classify the participants into three groups: people with mild cognitive impairment, people with Alzheimer's disease and healthy individuals as a control group. Then, the language performance of patients in the mild cognitive impairment and Alzheimer's disease groups was investigated and compared with those of the control group by using the Barnes Language Assessment. The groups were reassessed 6 months later to see if there was any change in language ability. Results The results showed that the mild cognitive impairment group and Alzheimer's disease group had significant decreases in expressive language (P>0.01), executive function (P>0.01), receptive language (P>0.01) and memory skills (P>0.01) from baseline to the reassessment at 6 months. Conclusions Language deficits, especially expressive language deficits, could appear before impairment in executive function, receptive language and verbal episodic memory in participants with mild cognitive impairment or Alzheimer's disease. Speech and language therapists can use the findings of this study to design and implement treatment programmes.

Strong Link Found Between Anxiety, Cognitive Impairment

Mild cognitive impairment (MCI) is a clinical concept proposed as an intermediate state between normal aging and dementia. This condition has multiple heterogeneous sources, including clinical presentation, etiology, and prognosis. Recently, the prevalence and associated features of neuropsychiatric symptoms (NPS) in MCI have been described. We systematically searched the PubMed database (last accessed on August 31, 2008) for articles on NPS in MCI. Included articles used strict selection criteria, and outcome variables were extracted in duplicate; of the 27 articles included, 14 (52%) used prospective cohorts. The global prevalence of NPS in MCI ranged from 35% to 85%. The most common behavioral symptoms were depression, anxiety, and irritability. Hospital-based samples reported a higher global prevalence of NPS than population-based studies; this discrepancy probably reflected differences in demographics, study setting, MCI diagnostic criteria, and behavioral instruments used. Prospective studies showed that NPS, particularly depression, may represent risk factors for MCI or predictors for the conversion of MCI to Alzheimer's disease (AD). NPS are very prevalent in subjects with MCI, displaying a similar pattern of symptoms compared to dementia and AD. Large cohort studies using standardized MCI criteria and behavioral instruments are required to evaluate the prognostic role of NPS in MCI.

Day-to-day life involves the perception of events that resemble one another. For the sufficient encoding and retrieval of similar information, the hippocampus provides two essential computational processes. Pattern separation refers to the differentiation of overlapping memory representations, whereas pattern completion reactivates memories based on noisy or degraded input. Evidence from human and rodent studies suggest that pattern separation specifically relies on neuronal ensemble activity in hippocampal subnetworks in the dentate gyrus and CA3. Although a role for CA1 in pattern separation has been shown in animal models, its contribution in the human hippocampus remains elusive. In order to elucidate the contribution of CA1 neurons to pattern separation, we examined 14 patients with an acute transient global amnesia (TGA), a rare self-limiting dysfunction of the hippocampal system showing specific lesions to CA1. Patients' pattern separation performance was tested during the acute amnestic phase and follow-up using an established mnemonic similarity test. Patients in the acute phase showed a profound deficit in pattern separation (p < .05) as well as recognition memory (p < .001) that recovered during follow-up. Specifically, patients tested in a later stage of the amnesia were less impaired in pattern separation than in recognition memory. Considering the time dependency of lesion-associated hippocampal deficits in early and late acute stages of the TGA, we showed that the pattern separation function recovered significantly earlier than recognition memory. Our results provide causal evidence that hippocampal CA1 neurons are critical to pattern separation performance in humans.

BackgroundThe 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&lt;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.