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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.
Highly selective positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for improving cognitive function in patients suffering from Alzheimer's disease and schizophrenia. However, excessive activation of M is known to induce seizure activity and have actions in the prefrontal cortex (PFC) that could impair cognitive function. We now report a series of pharmacological, electrophysiological, and behavioral studies in which we find that recently reported M PAMs, PF-06764427 and MK-7622, have robust agonist activity in cell lines and agonist effects in the mouse PFC, and have the potential to overactivate the M receptor and disrupt PFC function. In contrast, structurally distinct M PAMs (VU0453595 and VU0550164) are devoid of agonist activity in cell lines and maintain activity dependence of M activation in the PFC. Consistent with the previously reported effect of PF-06764427, the ago-PAM MK-7622 induces severe behavioral convulsions in mice. In contrast, VU0453595 does not induce behavioral convulsions at doses well above those required for maximal efficacy in enhancing cognitive function. Furthermore, in contrast to the robust efficacy of VU0453595, the ago-PAM MK-7622 failed to improve novel object recognition, a rodent assay of cognitive function. These findings suggest that in vivo cognition-enhancing efficacy of M PAMs can be observed with PAMs lacking intrinsic agonist activity and that intrinsic agonist activity of M PAMs may contribute to adverse effects and reduced efficacy in improving cognitive function.
Purpose - This investigation was conducted to determine whether young children with autism spectrum disorders exhibited a canonical neural response to word stimuli and whether putative event-related potential (ERP) measures of word processing were correlated with a concurrent measure of receptive language. Additional exploratory analyses were used to examine whether the magnitude of the association between ERP measures of word processing and receptive language varied as a function of the number of word stimuli the participants reportedly understood.
Method - Auditory ERPs were recorded in response to spoken words and nonwords presented with equal probability in 34 children aged 2-5 years with a diagnosis of autism spectrum disorder who were in the early stages of language acquisition. Average amplitudes and amplitude differences between word and nonword stimuli within 200-500 ms were examined at left temporal (T3) and parietal (P3) electrode clusters. Receptive vocabulary size and the number of experimental stimuli understood were concurrently measured using the MacArthur-Bates Communicative Development Inventories.
Results - Across the entire participant group, word-nonword amplitude differences were diminished. The average word-nonword amplitude difference at T3 was related to receptive vocabulary only if 5 or more word stimuli were understood.
Conclusions - If ERPs are to ever have clinical utility, their construct validity must be established by investigations that confirm their associations with predictably related constructs. These results contribute to accruing evidence, suggesting that a valid measure of auditory word processing can be derived from the left temporal response to words and nonwords. In addition, this measure can be useful even for participants who do not reportedly understand all of the words presented as experimental stimuli, though it will be important for researchers to track familiarity with word stimuli in future investigations.
Supplemental Material - https://doi.org/10.23641/asha.5614840.
Adjuvant chemotherapy has been used for decades to treat cancer, and it is well known that disruptions in cognitive function and memory are common chemotherapeutic adverse effects. However, studies using neuropsychological metrics have also reported group differences in cognitive function and memory before or without chemotherapy, suggesting that complex factors obscure the true etiology of chemotherapy-induced cognitive dysfunction (CICD) in humans. Therefore, to better understand possible mechanisms of CICD, we explored the effects of CICD in rats through cognition testing using novel object recognition (NOR) and contextual fear conditioning (CFC), and through metabolic neuroimaging via [F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Cancer-naïve, female Sprague-Dawley rats were administered either saline (1 mL/kg) or doxorubicin (DOX) (1 mg/kg in a volume of 1 mL/kg) weekly for five weeks (total dose = 5 mg/kg), and underwent cognition testing and PET imaging immediately following the treatment regime and 30 days post treatment. We did not observe significant differences with CFC testing post-treatment for either group. However, the chemotherapy group exhibited significantly decreased performance in the NOR test and decreased F-FDG uptake only in the prefrontal cortex 30 days post-treatment. These results suggest that long-term impairment within the prefrontal cortex is a plausible mechanism of CICD in this study, suggesting DOX-induced toxicity in the prefrontal cortex at the dose used.
While much research has focused on understanding how individual stimuli are encoded in episodic memory, less is known about how a series of events is bound into a coherent episode. Cognitive models of episodic memory propose that information about presented stimuli is integrated into a composite representation reflecting one's past experience, allowing events separated in time to become associated. Recent evidence suggests that neural oscillatory activity may be critically involved in this process. To examine how oscillatory activity contributes to binding of information across events, we measured scalp EEG as participants studied categorized lists of people, places, and objects. We assessed their memory for the lists using free recall, allowing us to characterize the temporal and semantic organization of the studied items in memory. Using pattern classification, we identified EEG activity during encoding at a range of frequencies and scalp locations that was sensitive to the category of presented stimuli. In the beta band (16-25Hz) at right posterior electrodes, we observed activity that was also sensitive to the category of recently presented stimuli. This neural activity showed two characteristics consistent with a representation of the recent past: It became stronger when multiple items from the same category were presented in succession, and it contained a fading trace of the previous category after a category shift. When items were separated by an inter-item distraction task, this integrative beta-band activity was disrupted. Distraction also led to decreased semantic organization of the studied materials without affecting their temporal organization; this suggests that distraction disrupts the integration of semantic information over time, preventing encoding of items in terms of the semantic context of earlier items. Our results provide evidence that beta-band activity is involved in maintaining information about recent events, allowing construction of a coherent representation of a temporally extended episode in memory.
Copyright © 2017 Elsevier Inc. All rights reserved.
Abnormalities in the signaling of the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) within cortical and limbic brain regions are thought to underlie many of the complex cognitive and affective symptoms observed in individuals with schizophrenia. The M muscarinic acetylcholine receptor (mAChR) subtype is a closely coupled signaling partner of the NMDAR. Accumulating evidence suggests that development of selective positive allosteric modulators (PAMs) of the M receptor represent an important treatment strategy for the potential normalization of disruptions in NMDAR signaling in patients with schizophrenia. In the present studies, we evaluated the effects of the novel and highly potent M PAM, VU6004256, in ameliorating selective prefrontal cortical (PFC)-mediated physiologic and cognitive abnormalities in a genetic mouse model of global reduction in the NR1 subunit of the NMDAR (NR1 knockdown [KD]). Using slice-based extracellular field potential recordings, deficits in muscarinic agonist-induced long-term depression (LTD) in layer V of the PFC in the NR1 KD mice were normalized with bath application of VU6004256. Systemic administration of VU6004256 also reduced excessive pyramidal neuron firing in layer V PFC neurons in awake, freely moving NR1 KD mice. Moreover, selective potentiation of M by VU6004256 reversed the performance impairments of NR1 KD mice observed in two preclinical models of PFC-mediated learning, specifically the novel object recognition and cue-mediated fear conditioning tasks. VU6004256 also produced a robust, dose-dependent reduction in the hyperlocomotor activity of NR1 KD mice. Taken together, the current findings provide further support for M PAMs as a novel therapeutic approach for the PFC-mediated impairments in schizophrenia.
Syntactic processing deficits are highly variable in individuals with primary progressive aphasia. Damage to left inferior frontal cortex has been associated with syntactic deficits in primary progressive aphasia in a number of structural and functional neuroimaging studies. However, a contrasting picture of a broader syntactic network has emerged from neuropsychological studies in other aphasic cohorts, and functional imaging studies in healthy controls. To reconcile these findings, we used functional magnetic resonance imaging to investigate the functional neuroanatomy of syntactic comprehension in 51 individuals with primary progressive aphasia, composed of all clinical variants and a range of degrees of syntactic processing impairment. We used trial-by-trial reaction time as a proxy for syntactic processing load, to determine which regions were modulated by syntactic processing in each patient, and how the set of regions recruited was related to whether syntactic processing was ultimately successful or unsuccessful. Relationships between functional abnormalities and patterns of cortical atrophy were also investigated. We found that the individual degree of syntactic comprehension impairment was predicted by left frontal atrophy, but also by functional disruption of a broader syntactic processing network, comprising left posterior frontal cortex, left posterior temporal cortex, and the left intraparietal sulcus and adjacent regions. These regions were modulated by syntactic processing in healthy controls and in patients with primary progressive aphasia with relatively spared syntax, but they were modulated to a lesser extent or not at all in primary progressive aphasia patients whose syntax was relatively impaired. Our findings suggest that syntactic comprehension deficits in primary progressive aphasia reflect not only structural and functional changes in left frontal cortex, but also disruption of a wider syntactic processing network.
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One theory of age-related cognitive decline proposes that changes within the default mode network (DMN) of the brain impact the ability to successfully perform cognitive operations. To investigate this theory, we examined functional covariance within brain networks using regional cerebral blood flow data, measured by O-water PET, from 99 participants (mean baseline age 68.6 ± 7.5) in the Baltimore Longitudinal Study of Aging collected over a 7.4 year period. The sample was divided in tertiles based on longitudinal performance on a verbal recognition memory task administered during scanning, and functional covariance was compared between the upper (improvers) and lower (decliners) tertile groups. The DMN and verbal memory networks (VMN) were then examined during the verbal memory scan condition. For each network, group differences in node-to-network coherence and individual node-to-node covariance relationships were assessed at baseline and in change over time. Compared with improvers, decliners showed differences in node-to-network coherence and in node-to-node relationships in the DMN but not the VMN during verbal memory. These DMN differences reflected greater covariance with better task performance at baseline and both increasing and declining covariance with declining task performance over time for decliners. When examined during the resting state alone, the direction of change in DMN covariance was similar to that seen during task performance, but node-to-node relationships differed from those observed during the task condition. These results suggest that disengagement of DMN components during task performance is not essential for successful cognitive performance as previously proposed. Instead, a proper balance in network processes may be needed to support optimal task performance.
Face recognition is fundamental to successful social interaction. Individuals with deficits in face recognition are likely to have social functioning impairments that may lead to heightened risk for social anxiety. A critical component of social interaction is how quickly a face is learned during initial exposure to a new individual. Here, we used a novel Repeated Faces task to assess how quickly memory for faces is established. Face recognition was measured over multiple exposures in 52 young adults ranging from low to high in social inhibition, a core dimension of social anxiety. High social inhibition was associated with a smaller slope of change in recognition memory over repeated face exposure, indicating participants with higher social inhibition showed smaller improvements in recognition memory after seeing faces multiple times. We propose that impaired face learning is an important mechanism underlying social inhibition and may contribute to, or maintain, social anxiety.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Are face and object recognition abilities independent? Although it is commonly believed that they are, Gauthier et al. [Gauthier, I., McGugin, R. W., Richler, J. J., Herzmann, G., Speegle, M., & VanGulick, A. E. Experience moderates overlap between object and face recognition, suggesting a common ability. Journal of Vision, 14, 7, 2014] recently showed that these abilities become more correlated as experience with nonface categories increases. They argued that there is a single underlying visual ability, v, that is expressed in performance with both face and nonface categories as experience grows. Using the Cambridge Face Memory Test and the Vanderbilt Expertise Test, they showed that the shared variance between Cambridge Face Memory Test and Vanderbilt Expertise Test performance increases monotonically as experience increases. Here, we address why a shared resource across different visual domains does not lead to competition and to an inverse correlation in abilities? We explain this conundrum using our neurocomputational model of face and object processing ["The Model", TM, Cottrell, G. W., & Hsiao, J. H. Neurocomputational models of face processing. In A. J. Calder, G. Rhodes, M. Johnson, & J. Haxby (Eds.), The Oxford handbook of face perception. Oxford, UK: Oxford University Press, 2011]. We model the domain general ability v as the available computational resources (number of hidden units) in the mapping from input to label and experience as the frequency of individual exemplars in an object category appearing during network training. Our results show that, as in the behavioral data, the correlation between subordinate level face and object recognition accuracy increases as experience grows. We suggest that different domains do not compete for resources because the relevant features are shared between faces and objects. The essential power of experience is to generate a "spreading transform" for faces (separating them in representational space) that generalizes to objects that must be individuated. Interestingly, when the task of the network is basic level categorization, no increase in the correlation between domains is observed. Hence, our model predicts that it is the type of experience that matters and that the source of the correlation is in the fusiform face area, rather than in cortical areas that subserve basic level categorization. This result is consistent with our previous modeling elucidating why the FFA is recruited for novel domains of expertise [Tong, M. H., Joyce, C. A., & Cottrell, G. W. Why is the fusiform face area recruited for novel categories of expertise? A neurocomputational investigation. Brain Research, 1202, 14-24, 2008].