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Relational memory, or the ability to form contextual associations among items encountered closely in time, is impaired in schizophrenia. The ability to bind items into a relational memory is dependent on the hippocampus, a region that is abnormal in schizophrenia. However, the hippocampus is also involved in exploratory behavior, leaving open the question whether relational memory deficits in schizophrenia are due to failure of relational binding or diminished visual exploration of individual items during encoding. We studied visual exploration patterns during the encoding of face-scene pairs in 66 healthy control subjects and 69 early psychosis patients, to test the hypothesis that differences in visual exploration during the encoding phase can explain task accuracy differences between the two groups. Psychosis patients had lower explicit test accuracy and were less likely to transition from mouth to eyes during encoding. The visual exploration pattern differences between groups did not mediate the relationship between group and explicit test accuracy. We conclude that early psychosis patients have an abnormal pattern of binding items together during encoding that warrants further research.
Copyright © 2020 Elsevier B.V. All rights reserved.
BACKGROUND - Learning and memory are impaired in schizophrenia. Some theories have proposed that one form of memory, habituation, is particularly impaired. Preliminary evidence suggests that memory impairment is associated with failed hippocampal habituation in patients with chronic schizophrenia. We studied how abnormal habituation of the hippocampus is related to relational memory deficits in the early stage of psychosis.
METHODS - We measured hippocampal activity in 62 patients with early psychosis and 70 healthy individuals using functional magnetic resonance imaging. Habituation was defined as the slope of functional magnetic resonance imaging signal change to repeated presentations of faces and objects. Relational memory ability was measured as the slope of preferential viewing during a face-scene pair eye movement task outside the scanner.
RESULTS - Patients with early psychosis showed impaired relational memory (p < .001) and less hippocampal habituation to objects (p = .01) than healthy control subjects. In the healthy control group, better relational memory was associated with faster anterior hippocampal habituation (faces, r = -.28, p = .03). In contrast, patients with early psychosis showed no brain-behavior relationship (r = .12, p = .40).
CONCLUSIONS - We found evidence for disrupted hippocampal habituation in the early stage of psychosis along with an altered association between hippocampal habituation and relational memory ability. These results suggest that neural habituation may provide a novel target for early cognitive interventions in psychosis.
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Humans constantly take in vast amounts of information, which must be filtered, flexibly manipulated, and integrated into cohesive relational memories in order to choose relevant behaviors. Relational memory is impaired in chronic schizophrenia, which has been linked to hippocampal dysfunction. It is unclear whether relational memory is impaired in the early stage of psychosis.
METHODS - We studied eye movements during a face-scene pairs task as an indirect measure of relational memory in 89 patients in the early stage of psychosis and 84 healthy control participants. During testing, scenes were overlaid with three equally-familiar faces and participants were asked to recall the matching (i.e. previously-paired) face. During Match trials, one face had been previously paired with the scene. During Non-Match trials, no faces matched the scene. Forced-choice explicit recognition was recorded as a direct measure of relational memory.
RESULTS - Healthy control subjects rapidly (within 250-500 ms) showed preferential viewing of the matching face during Match trials. In contrast, preferential viewing was delayed in patients in the early stage of psychosis. Explicit recognition of the matching face was also impaired in the patient group.
CONCLUSIONS - This study provides novel evidence for a relational memory deficit in the early stage of psychosis. Patients showed deficits in both explicit recognition as well as abnormal eye-movement patterns during memory recall. Eye movements provide a promising avenue for the study of relational memory in psychosis, as they allow for the assessment of rapid, nonverbal memory processes.
Copyright © 2019 Elsevier B.V. All rights reserved.
The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by semantic memory deficits with relatively preserved motor speech, syntax, and phonology. There is consistent evidence linking focal neurodegeneration of the anterior temporal lobes (ATL) to the semantic deficits observed in svPPA. Less is known about large-scale functional connectivity changes in this syndrome, particularly regarding the interplay between affected and spared language networks that leads to the unique cognitive dissociations typical of svPPA. Using whole-brain, seed-based connectivity on task-free Magnetic Resonance Imaging (MRI) data, we studied connectivity of networks anchored to three left-hemisphere regions crucially involved in svPPA symptomatology: ATL just posterior to the main atrophic area, opercular inferior frontal gyrus, and posterior inferior temporal lobe. First, in 32 healthy controls, these seeds isolated three networks: a ventral semantic network involving anterior middle temporal and angular gyri, a dorsal articulatory-phonological system involving inferior frontal and supramarginal regions, and a third functional connection between posterior inferior temporal and intraparietal regions likely involved in linking visual and linguistic processes. We then compared connectivity strength of these three networks between 16 svPPA patients and the 32 controls. In svPPA, decreased functional connectivity in the ventral semantic network correlated with weak semantic skills, while connectivity of the network seeded from the posterior inferior temporal lobe, though not significantly different between the two groups, correlated with pseudoword reading skills. Increased connectivity between the inferior frontal gyrus and the superior portion of the angular gyrus suggested possible adaptive changes. Our findings have two main implications. First, they support a functional subdivision of the left IPL based on its connectivity to specific language-related regions. Second, the unique neuroanatomical and linguistic profile observed in svPPA provides a compelling model for the functional interplay of these networks, being either up- or down- regulated in response to disease.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
β-Site APP (amyloid precursor protein) cleaving enzyme 1 (BACE1) is the β-secretase enzyme that initiates production of the toxic amyloid-β peptide that accumulates in the brains of patients with Alzheimer's disease (AD). Hence, BACE1 is a prime therapeutic target, and several BACE1 inhibitor drugs are currently being tested in clinical trials for AD. However, the safety of BACE1 inhibition is unclear. Germline BACE1 knockout mice have multiple neurological phenotypes, although these could arise from BACE1 deficiency during development. To address this question, we report that tamoxifen-inducible conditional BACE1 knockout mice in which the gene was ablated in the adult largely lacked the phenotypes observed in germline BACE1 knockout mice. However, one BACE1-null phenotype was induced after gene deletion in the adult mouse brain. This phenotype showed reduced length and disorganization of the hippocampal mossy fiber infrapyramidal bundle, the axonal pathway of dentate gyrus granule cells that is maintained by neurogenesis in the mouse brain. This defect in axonal organization correlated with reduced BACE1-mediated cleavage of the neural cell adhesion protein close homolog of L1 (CHL1), which has previously been associated with axon guidance. Although our results indicate that BACE1 inhibition in the adult mouse brain may avoid phenotypes associated with BACE1 deficiency during embryonic and postnatal development, they also suggest that BACE1 inhibitor drugs developed for treating AD may disrupt the organization of an axonal pathway in the hippocampus, an important structure for learning and memory.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
BACKGROUND - Functional dysconnectivity has been proposed as a major pathophysiological mechanism for cognitive dysfunction in schizophrenia. The hippocampus is a focal point of dysconnectivity in schizophrenia, with decreased hippocampal functional connectivity contributing to the marked memory deficits observed in patients. Normal memory function relies on the interaction of complex corticohippocampal networks. However, only recent technological advances have enabled the large-scale exploration of functional networks with accuracy and precision.
METHODS - We investigated the modularity of hippocampal resting-state functional networks in a sample of 45 patients with schizophrenia spectrum disorders and 38 healthy control subjects. Modularity was calculated for two distinct functional networks: a core hippocampal-medial temporal lobe cortex network and an extended hippocampal-cortical network. As hippocampal function differs along its longitudinal axis, follow-up analyses examined anterior and posterior networks separately. To explore effects of resting network function on behavior, we tested associations between modularity and relational memory ability. Age, sex, handedness, and parental education were similar between groups.
RESULTS - Network modularity was lower in schizophrenia patients, especially in the posterior hippocampal network. Schizophrenia patients also showed markedly lower relational memory ability compared with control subjects. We found a distinct brain-behavior relationship in schizophrenia that differed from control subjects by network and anterior/posterior division-while relational memory in control subjects was associated with anterior hippocampal-cortical modularity, schizophrenia patients showed an association with posterior hippocampal-medial temporal lobe cortex network modularity.
CONCLUSIONS - Our findings support a model of abnormal resting-state corticohippocampal network coherence in schizophrenia, which may contribute to relational memory deficits.
Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Working memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined.
OBJECTIVE - The current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI).
METHODS - Memory clinic patients (n = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied.
RESULTS - A 3 (group)×5 (serial position) repeated measures ANOVA yielded a significant group×trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non-MCI patients for serial position 3 (p < 0.003) serial position 4 (p < 0.002); and lower than both group for serial position 5 (recency; p < 0.002). Mixed/dys MCI patients also produced more transposition errors than both groups (p < 0.010); and more omissions (p < 0.020), and perseverations errors (p < 0.018) than non-MCI patients.
CONCLUSIONS - The attenuation of a recency effect using serial order parameters obtained from the BDT may provide a useful operational definition as well as additional diagnostic information regarding working memory deficits in MCI.
Although selective activation of the M muscarinic acetylcholine receptor (mAChR) subtype has been shown to improve cognitive function in animal models of neuropsychiatric disorders, recent evidence suggests that enhancing M mAChR function can also improve memory performance. Positive allosteric modulators (PAMs) targeting the M mAChR subtype have shown therapeutic potential for the treatment of multiple symptoms observed in schizophrenia, including positive and cognitive symptoms when assessed in acute preclinical dosing paradigms. Since the cholinergic system has been implicated in multiple stages of learning and memory, we evaluated the effects of repeated dosing with the highly selective M PAM VU0467154 on either acquisition and/or consolidation of learning and memory when dosed alone or after pharmacologic challenge with the N-methyl-d-aspartate subtype of glutamate receptors (NMDAR) antagonist MK-801. MK-801 challenge represents a well-documented preclinical model of NMDAR hypofunction that is thought to underlie some of the positive and cognitive symptoms observed in schizophrenia. In wildtype mice, 10-day, once-daily dosing of VU0467154 either prior to, or immediately after daily testing enhanced the rate of learning in a touchscreen visual pairwise discrimination task; these effects were absent in M mAChR knockout mice. Following a similar 10-day, once-daily dosing regimen of VU0467154, we also observed 1) improved acquisition of memory in a cue-mediated conditioned freezing paradigm, 2) attenuation of MK-801-induced disruptions in the acquisition of memory in a context-mediated conditioned freezing paradigm and 3) reversal of MK-801-induced hyperlocomotion. Comparable efficacy and plasma and brain concentrations of VU0467154 were observed after repeated dosing as those previously reported with an acute, single dose administration of this M PAM. Together, these studies are the first to demonstrate that cognitive enhancing and antipsychotic-like activity are not subject to the development of tolerance following repeated dosing with a selective M PAM in mice and further suggest that activation of M mAChRs may modulate both acquisition and consolidation of memory functions.
Copyright © 2017 Elsevier Ltd. All rights reserved.
With successful antiretroviral therapy in the US, HIV-positive adults now routinely survive into old age. However, increased life expectancy with HIV introduces the added complication of age-related cognitive decline. Aging with HIV has been associated with poorer cognitive outcomes compared to HIV-negative adults. While up to 50% of older HIV-positive adults will develop some degree of cognitive impairment over their lifetime, cognitive symptoms are often not consistently monitored, until those symptoms are significant enough to impair daily life. In this study we found that subjective memory complaint (SMC) ratings correlated with measurable memory performance impairments in HIV-positive adults, but not HIV-negative adults. As the HIV-positive population ages, structured subjective cognitive assessment may be beneficial to identify the early signs of cognitive impairment, and subsequently allow for earlier interventions to maintain cognitive performance as these adults continue to survive into old age.
Alzheimer's disease (AD) biomarkers and stroke risk factors independently predict cognitive impairment, likely through independent disease pathways. However, limited work has sought to describe the dynamic interplay between these important risk factors. This article evaluated the interaction between stroke risk and AD biomarkers on hippocampal volume and cognitive performance. We first evaluated the interaction between stroke risk factors and AD biomarkers using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1202). We then extended our findings to an independent autopsy data set from the National Alzheimer's Coordinating Center (NACC, n = 1122) using measures of AD pathology. Stroke risk was quantified using the Framingham Stroke Risk Profile. In ADNI, stroke risk interacted with tau and amyloid levels in relation to baseline and longitudinal cognitive performance. Similarly, in NACC, stroke risk interacted with amyloid and tau positivity on cognitive performance. The effect of stroke risk factors on cognition was strongest in the absence of AD biomarkers or neuropathology, providing additional evidence that AD biomarkers and stroke risk factors relate to cognition through independent pathways.
Copyright © 2015 Elsevier Inc. All rights reserved.