S177. IMPACT OF NOS1AP AND ITS INTERACTION PARTNERS AT THE GLUTAMATERGIC SYNAPSE ON WORKING MEMORY NETWORKS - AN FMRI IMAGING GENETICS STUDY

Abstract Background N-methyl-D-aspartate receptor (NMDAR) hypofunction is an important pathophysiological mechanism in schizophrenia. At the postsynapse the NMDAR interacts with the post-synaptic density (PSD). Neuronal nitric oxide synthase 1 (NOS1) binds to the PSD scaffolding proteins PSD-93 and PSD-95, enabling NMDAR-mediated release of nitric oxide via NOS1. NOS1AP (adaptor of NOS1) is capable of disrupting the interactions between NOS1, PSD-93, and PSD95. Therefore, NOS1AP is closely involved in both glutamatergic and nitrinergic neurotransmission. NOS1AP has been implicated as a risk gene for schizophrenia and cognitive dysfunction. Its increased expression has been observed in dorsolateral prefrontal post-mortem brain tissue of patients with schizophrenia, and NOS1AP SNPs have been associated with established schizophrenia endophenotypes. These findings suggest that the influence of NOS1AP variants should be observable in neural systems implicated in schizophrenia. In the present study, we investigate the impact of NOS1AP and its interaction partners at the glutamatergic synapse on the cortical working memory (WM) networks using fMRI and a gene set analysis approach. Methods 97 right-handed individuals with no personal or family history of psychiatric disorders underwent fMRI in a 3T Siemens Trio scanner during the performance of a visuospatial change detection WM task. Data analysis in Brain Voyager QX 2.8 included standard data preprocessing. Additionally, a multiscale curvature driven cortex based alignment procedure was used to minimize macro-anatomical variability between subjects. Subsequently, data were analyzed using a random-effects multi-subject general linear model. We investigated 19 regions of interest (ROIs) within the core fronto-parietal WM network. We studied all phases of our WM paradigm (encoding, maintenance, retrieval), which were modeled by a total of 5 regressors (encoding, delays 1–3, retrieval). Genetic data was quality controlled and imputed using the RICOPILI pipeline. Gene-set analyses of the 19 ROIs were performed using MAGMA. Two gene sets were selected: 1) NOS1AP/NOS1; 2) NOS1AP/glutamatergic synapse. We applied a Bonferroni correction for the total of 19 ROIs and 5 regressors (95 tests) to both analyses. Results Both gene set analyses revealed multiple associations between brain activation in core fronto-parietal WM areas. For the NOS1/NOS1AP set, most associations were observed during the late maintenance phase (Delay 3) of our WM paradigm. One association was significant Bonferroni correction: a cluster in the left intraparietal sulcus during the late maintenance phase (Delay 3; β=2.2459, SD=0.0239, SE=0.6451, p=0,00025). For NOS1AP / glutamatergic synapse interaction partners, two associations were significant after Bonferroni correction: a cluster in the right IPS during the early maintenance phase (Delay 1; β=0.8525, SD=0.0257, SE=0.2127, p=0.0000308) and a cluster in a different part of the right IPS during the late maintenance phase (Delay 3; β=0.7186, SD=0.0216, SE=0.2119, p=0,000348). Discussion In our gene set analyses we observed multiple associations between brain activation during WM and NOS1AP and its interaction partners, which were most pronounced during the late maintenance phase of our WM task in bilateral areas within the IPS. Both the more constrained NOS1AP / NOS1 gene set and the NOS1AP / glutamatergic synapse gene set showed similar association patterns. Our results implicate the NOS1AP interactome and the glutamatergic system in information processing and brain function in a cognitive domain strongly impaired in schizophrenia. They also indicate that altered activation of parietal WM areas during the maintenance phase is most strongly affected.

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Brain Activation and Psychophysiologic Interaction in Association with a Phonological Working Memory Task

Modern Applied Science ◽

10.5539/mas.v8n5p97 ◽

2014 ◽

Vol 8 (5) ◽

pp. 97 ◽

Cited By ~ 1

Author(s):

Ahmad Nazlim Yusoff ◽

Hanani Abdul Manan ◽

Siti Zamratol-Mai Sarah Mukari ◽

Khairiah Abdul Hamid ◽

Elizabeth A. Franz

Keyword(s):

Working Memory ◽

Temporal Lobe ◽

Speech Processing ◽

Source Region ◽

Memory Task ◽

Brain Activation ◽

Phonological Working Memory ◽

Babble Noise ◽

The Right ◽

The Brain

Brain activation within, and psychophysiologic interaction between, significantly activated regions in the brain obtained from a phonological working memory experiment on a single participant were studied. Given that working memory and speech processing are key functions of human behaviour, this type of investigation is of fundamental importance to our understanding of brain-behaviour relationships. The study objectives were to determine the areas that respond significantly to a phonological working memory task and to investigate the influence of babble noise on their activation and the psychophysiologic interactions (PPI) between the source region and those activated areas. Three conditions were used during functional magnetic resonance imaging (fMRI) scans which were working memory in quiet (WMQ), working memory in noise (WMN) and listening to babble noise (N). More voxels are activated in the right temporal lobe than in the left during N condition due to the non-speech stimulus. However, a higher mean stimulus efficacy (?) of the point of maximum intensity in the left temporal lobe causes its signal intensity to be higher than in the right temporal lobe. Both the WMQ and WMN conditions resulted in similar activated regions in the brain but with a higher number of activated voxels (NOV) during WMQ for the right hemispheric areas in association with the working memory task. This is due to the sensitivity of those regions in perceiving and performing the phonological working memory task in quiet to a level that actually exceeds the activation enhancement commonly associated with the performance of working memory task in noise. This is supported by the PPI results that performing the working memory task is less influenced by noise for that particular brain region.

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Working memory dysfunction in schizophrenia patients with obsessive-compulsive symptoms: An fMRI study

European Psychiatry ◽

10.1016/j.eurpsy.2013.02.004 ◽

2014 ◽

Vol 29 (3) ◽

pp. 160-166 ◽

Cited By ~ 24

Author(s):

M. Bleich-Cohen ◽

T. Hendler ◽

R. Weizman ◽

S. Faragian ◽

A. Weizman ◽

...

Keyword(s):

Working Memory ◽

Brain Activation ◽

Distinct Pattern ◽

Obsessive Compulsive ◽

Similar Reduction ◽

Activation Patterns ◽

Compulsive Disorder ◽

Fmri Study ◽

Dorsolateral Prefrontal ◽

The Right

AbstractBackground:A substantial proportion of schizophrenia patients also meets DSM-IV criteria for obsessive-compulsive disorder (OCD). Schizophrenia with OCD (“schizo-obsessive”) patients are characterized by distinct clinical characteristics, treatment response and prognosis. Whether schizo-obsessive patients exhibit a distinct pattern of brain activation is yet unknown. To address this question, the present functional magnetic resonance imaging (fMRI) study explicitly compared alterations in brain activation and functional connectivity (FC) underlying a working memory deficit in schizophrenia patients with and without OCD.Methods:fMRI was applied during the N-back working memory (WM) task in three groups: schizo-obsessive (n = 16), schizophrenia (n = 17) and matched healthy volunteers (n = 20). WM-related activation in the right dorsolateral prefrontal cortex (DLPFC) and the right caudate nucleus, brain areas relevant to schizophrenia and OCD, and FC analysis were used for the evaluation.Results:The two schizophrenia groups with and without OCD exhibited a similar reduction in activation in the right DLPFC and right caudate, as well as decreased FC compared to the healthy controls. Notably, reduced regional brain activation was not related to severity of schizophrenic or OCD symptoms.Conclusions:Schizo-obsessive patients do not differ from their non-OCD schizophrenia counterparts in brain activation patterns during the N-back WM task. Cognitive paradigms taping alternative neural networks (e.g., orbitofrontal cortex) particularly relevant to OCD, are warranted in the search for potential distinctive brain activation patterns of the schizo-obsessive subgroup.

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Association between Hippocampal Volume and Working Memory in 10,000+ 9–10-Year-Old Children: Sex Differences

Children ◽

10.3390/children8050411 ◽

2021 ◽

Vol 8 (5) ◽

pp. 411

Author(s):

Shervin Assari ◽

Shanika Boyce ◽

Tanja Jovanovic

Keyword(s):

Working Memory ◽

Sex Differences ◽

Parental Education ◽

Predictor Variable ◽

National Sample ◽

Hippocampal Volume ◽

Study Data ◽

Cross Sectional ◽

The Right

Aim: This study tested sex differences in the association between hippocampal volume and working memory of a national sample of 9–10-year-old children in the US. As the hippocampus is functionally lateralized (especially in task-related activities), we explored the results for the right and the left hippocampus. Methods: This is a cross-sectional study using the Adolescent Brain Cognitive Development (ABCD) Study data. This analysis included baseline ABCD data (n = 10,093) of children between ages 9 and 10 years. The predictor variable was right and left hippocampal volume measured by structural magnetic resonance imaging (sMRI). The primary outcome, list sorting working memory, was measured using the NIH toolbox measure. Sex was the moderator. Age, race, ethnicity, household income, parental education, and family structure were the covariates. Results: In the overall sample, larger right (b = 0.0013; p < 0.001) and left (b = 0.0013; p < 0.001) hippocampal volumes were associated with higher children’s working memory. Sex had statistically significant interactions with the right (b = −0.0018; p = 0.001) and left (b = −0.0012; p = 0.022) hippocampal volumes on children’s working memory. These interactions indicated stronger positive associations between right and left hippocampal volume and working memory for females compared to males. Conclusion: While right and left hippocampal volumes are determinants of children’s list sorting working memory, these effects seem to be more salient for female than male children. Research is needed on the role of socialization, sex hormones, and brain functional connectivity as potential mechanisms that may explain the observed sex differences in the role of hippocampal volume as a correlate of working memory.

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Are visual working memory and episodic memory distinct processes? Insight from stroke patients by lesion-symptom mapping

Brain Structure and Function ◽

10.1007/s00429-021-02281-0 ◽

2021 ◽

Author(s):

Selma Lugtmeijer ◽

◽

Linda Geerligs ◽

Frank Erik de Leeuw ◽

Edward H. F. de Haan ◽

...

Keyword(s):

Working Memory ◽

Episodic Memory ◽

Visual Working Memory ◽

Visual Memory ◽

Right Hemisphere ◽

Memory Task ◽

Stroke Patients ◽

Lesion Symptom Mapping ◽

Criterion Setting ◽

The Right

AbstractWorking memory and episodic memory are two different processes, although the nature of their interrelationship is debated. As these processes are predominantly studied in isolation, it is unclear whether they crucially rely on different neural substrates. To obtain more insight in this, 81 adults with sub-acute ischemic stroke and 29 elderly controls were assessed on a visual working memory task, followed by a surprise subsequent memory test for the same stimuli. Multivariate, atlas- and track-based lesion-symptom mapping (LSM) analyses were performed to identify anatomical correlates of visual memory. Behavioral results gave moderate evidence for independence between discriminability in working memory and subsequent memory, and strong evidence for a correlation in response bias on the two tasks in stroke patients. LSM analyses suggested there might be independent regions associated with working memory and episodic memory. Lesions in the right arcuate fasciculus were more strongly associated with discriminability in working memory than in subsequent memory, while lesions in the frontal operculum in the right hemisphere were more strongly associated with criterion setting in subsequent memory. These findings support the view that some processes involved in working memory and episodic memory rely on separate mechanisms, while acknowledging that there might also be shared processes.

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Brain Activation during Thoughts of One’s Own Death and Its Linear and Curvilinear Correlations with Fear of Death in Elderly Individuals: An fMRI Study

Cerebral Cortex Communications ◽

10.1093/texcom/tgab003 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Kanan Hirano ◽

Kentaro Oba ◽

Toshiki Saito ◽

Shohei Yamazaki ◽

Ryuta Kawashima ◽

...

Keyword(s):

Brain Activation ◽

Posterior Cingulate Cortex ◽

Fear Of Death ◽

Supramarginal Gyrus ◽

Brain Responses ◽

Fmri Study ◽

Negative Linear Correlation ◽

The Right ◽

Older Populations ◽

Existential Issues

Abstract Facing one’s own death and managing the fear of death are important existential issues, particularly in older populations. Although recent functional magnetic resonance imaging (fMRI) studies have investigated brain responses to death-related stimuli, none has examined whether this brain activation was specific to one’s own death or how it was related to dispositional fear of death. In this study, during fMRI, 34 elderly participants (aged, 60–72 years) were presented with either death-related or death-unrelated negative words and asked to evaluate the relevance of these words to the “self” or the “other.” The results showed that only the left supplementary motor area (SMA) was selectively activated during self-relevant judgments of death-related words. Regression analyses of the effect of fear of death on brain activation during death-related thoughts identified a significant negative linear correlation in the right supramarginal gyrus (SMG) and an inverted-U-shaped correlation in the posterior cingulate cortex (PCC) only during self-relevant judgments. Our results suggest potential involvement of the SMA in the existential aspect of thoughts of death. The distinct fear-of-death-dependent responses in the SMG and PCC may reflect fear-associated distancing of the physical self and the processing of death-related thoughts as a self-relevant future agenda, respectively.

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The role of prefrontal cortex in working memory: examining the contents of consciousness

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1998.0334 ◽

1998 ◽

Vol 353 (1377) ◽

pp. 1819-1828 ◽

Cited By ~ 159

Author(s):

◽

S. M. Courtney ◽

L. Petit ◽

J. V. Haxby ◽

L. G. Ungerleider

Keyword(s):

Working Memory ◽

Prefrontal Cortex ◽

Visual Processing ◽

Right Hemisphere ◽

Functional Organization ◽

Spatial Working Memory ◽

Domain Specificity ◽

Long Term Memory ◽

Present Evidence ◽

The Right

Working memory enables us to hold in our ‘mind's eye’ the contents of our conscious awareness, even in the absence of sensory input, by maintaining an active representation of information for a brief period of time. In this review we consider the functional organization of the prefrontal cortex and its role in this cognitive process. First, we present evidence from brain–imaging studies that prefrontal cortex shows sustained activity during the delay period of visual working memory tasks, indicating that this cortex maintains on–line representations of stimuli after they are removed from view. We then present evidence for domain specificity within frontal cortex based on the type of information, with object working memory mediated by more ventral frontal regions and spatial working memory mediated by more dorsal frontal regions. We also propose that a second dimension for domain specificity within prefrontal cortex might exist for object working memory on the basis of the type of representation, with analytic representations maintained preferentially in the left hemisphere and image–based representations maintained preferentially in the right hemisphere. Furthermore, we discuss the possibility that there are prefrontal areas brought into play during the monitoring and manipulation of information in working memory in addition to those engaged during the maintenance of this information. Finally, we consider the relationship of prefrontal areas important for working memory, both to posterior visual processing areas and to prefrontal areas associated with long–term memory.

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Abnormal prefrontal activity subserving attentional control of emotion in remitted depressed patients during a working memory task with emotional distracters

Psychological Medicine ◽

10.1017/s0033291711001097 ◽

2011 ◽

Vol 42 (1) ◽

pp. 29-40 ◽

Cited By ~ 60

Author(s):

R. Kerestes ◽

C. D. Ladouceur ◽

S. Meda ◽

P. J. Nathan ◽

H. P. Blumberg ◽

...

Keyword(s):

Working Memory ◽

Attentional Control ◽

Memory Load ◽

Memory Task ◽

Region Of Interest ◽

Blood Oxygen Level Dependent ◽

Emotional Information ◽

Working Memory Load ◽

Depressed Patients ◽

The Right

BackgroundPatients with major depressive disorder (MDD) show deficits in processing of facial emotions that persist beyond recovery and cessation of treatment. Abnormalities in neural areas supporting attentional control and emotion processing in remitted depressed (rMDD) patients suggests that there may be enduring, trait-like abnormalities in key neural circuits at the interface of cognition and emotion, but this issue has not been studied systematically.MethodNineteen euthymic, medication-free rMDD patients (mean age 33.6 years; mean duration of illness 34 months) and 20 age- and gender-matched healthy controls (HC; mean age 35.8 years) performed the Emotional Face N-Back (EFNBACK) task, a working memory task with emotional distracter stimuli. We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure neural activity in the dorsolateral (DLPFC) and ventrolateral prefrontal cortex (VLPFC), orbitofrontal cortex (OFC), ventral striatum and amygdala, using a region of interest (ROI) approach in SPM2.ResultsrMDD patients exhibited significantly greater activity relative to HC in the left DLPFC [Brodmann area (BA) 9/46] in response to negative emotional distracters during high working memory load. By contrast, rMDD patients exhibited significantly lower activity in the right DLPFC and left VLPFC compared to HC in response to positive emotional distracters during high working memory load. These effects occurred during accurate task performance.ConclusionsRemitted depressed patients may continue to exhibit attentional biases toward negative emotional information, reflected by greater recruitment of prefrontal regions implicated in attentional control in the context of negative emotional information.

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Distinguishable Brain Activation Networks for Short- and Long-Term Motor Skill Learning

Journal of Neurophysiology ◽

10.1152/jn.00717.2004 ◽

2005 ◽

Vol 94 (1) ◽

pp. 512-518 ◽

Cited By ~ 222

Author(s):

A. Floyer-Lea ◽

P. M. Matthews

Keyword(s):

Motor Skill ◽

Isometric Force ◽

Brain Activation ◽

Skill Learning ◽

Anterior Cingulate ◽

Motor Skill Learning ◽

Short Term ◽

Learning Stage ◽

The Right

The acquisition of a new motor skill is characterized first by a short-term, fast learning stage in which performance improves rapidly, and subsequently by a long-term, slower learning stage in which additional performance gains are incremental. Previous functional imaging studies have suggested that distinct brain networks mediate these two stages of learning, but direct comparisons using the same task have not been performed. Here we used a task in which subjects learn to track a continuous 8-s sequence demanding variable isometric force development between the fingers and thumb of the dominant, right hand. Learning-associated changes in brain activation were characterized using functional MRI (fMRI) during short-term learning of a novel sequence, during short-term learning after prior, brief exposure to the sequence, and over long-term (3 wk) training in the task. Short-term learning was associated with decreases in activity in the dorsolateral prefrontal, anterior cingulate, posterior parietal, primary motor, and cerebellar cortex, and with increased activation in the right cerebellar dentate nucleus, the left putamen, and left thalamus. Prefrontal, parietal, and cerebellar cortical changes were not apparent with short-term learning after prior exposure to the sequence. With long-term learning, increases in activity were found in the left primary somatosensory and motor cortex and in the right putamen. Our observations extend previous work suggesting that distinguishable networks are recruited during the different phases of motor learning. While short-term motor skill learning seems associated primarily with activation in a cortical network specific for the learned movements, long-term learning involves increased activation of a bihemispheric cortical-subcortical network in a pattern suggesting “plastic” development of new representations for both motor output and somatosensory afferent information.

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