Neural correlates of visuospatial working memory in the “at-risk mental state”. Psychol Med

Psychosis Clinical Academic Group, Institute of Psychiatry, King's College London, UK.
Psychological Medicine (Impact Factor: 5.94). 03/2010; 40(12):1987-99. DOI: 10.1017/S0033291710000280
Source: PubMed


Impaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia.
fMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 age-matched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object-location paired-associate memory task, with experimental manipulation of mnemonic load.
In all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS.
Abnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis.

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Available from: Matthew Richard Broome,
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    • "For example , Crossley et al. (2009) demonstrated a progressive increase in dysfunctional frontotemporal connectivity during a working memory task from HC to ARMS individuals and further to patients with FEP. Beyond connectivity, ARMS is also associated with abnormalities of regional brain structure (Fusar-Poli et al., 2012e; Smieskova et al., 2010), activity (Broome et al., 2010), and neurochemistry (Allen et al., 2012; Fusar-Poli et al., 2011b) that are qualitatively similar to but less severe than those in patients with overt psychosis (Fusar-Poli et al., 2007b). There is also evidence suggesting that within ARMS individuals, prefrontal dysfunction during WM is related to grey matter abnormalities in the same regions (Fusar-Poli et al., 2011a). "
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    ABSTRACT: The psychosis high-risk state is accompanied by alterations in functional brain activity during working memory processing. We used binary automatic pattern-classification to discriminate between the at-risk mental state (ARMS), first episode psychosis (FEP) and healthy controls (HCs) based on n-back WM-induced brain activity. Linear support vector machines and leave-one-out-cross-validation were applied to fMRI data of matched ARMS, FEP and HC (19 subjects/group). The HC and ARMS were correctly classified, with an accuracy of 76.2% (sensitivity 89.5%, specificity 63.2%, p = 0.01) using a verbal working memory network mask. Only 50% and 47.4% of individuals were classified correctly for HC vs. FEP (p = 0.46) or ARMS vs. FEP (p = 0.62), respectively. Without mask, accuracy was 65.8% for HC vs. ARMS (p = 0.03) and 65.8% for HC vs. FEP (p = 0.0047), and 57.9% for ARMS vs. FEP (p = 0.18). Regions in the medial frontal, paracingulate, cingulate, inferior frontal and superior frontal gyri, inferior and superior parietal lobules, and precuneus were particularly important for group separation. These results suggest that FEP and HC or FEP and ARMS cannot be accurately separated in small samples under these conditions. However, ARMS can be identified with very high sensitivity in comparison to HC. This might aid classification and help to predict transition in the ARMS.
    Clinical neuroimaging 10/2015; 9(9):555-563. DOI:10.1016/j.nicl.2015.09.015 · 2.53 Impact Factor
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    • "Previous compelling evidence from clinical studies suggested that cognitive impairment is intrinsic to schizophrenia, particularly within the domains of executive function, attention, and memory (Kuperberg and Heckers, 2000). Deficits in spatial learning and memory as well as spatial working memory have been consistently reported among schizophrenia patients, suggesting that these cognitive deficits are robust clinical features of schizophrenia (Broome et al., 2010; Ettinger et al., 2011; Mayer and Park, 2012; Zhang et al., 2012). On the basis of the MK-801 rat model, which replicates many of these clinical features, the primary aim of this study was to investigate the neuroplasticity mechanism of OLZ at work in the superior therapeutic effects on cognitive deficits usually observed in OLZ treatment among schizophrenia patients. "
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    ABSTRACT: Schizophrenia patients exhibit a wide range of impairments in cognitive functions. Clinically, atypical antipsychotic drugs (AAPs) such as olanzapine (OLZ) have a therapeutic effect on memory function among schizophrenia patients rather than typical antipsychotics, e.g., haloperidol. To date, however, little is known about the neuroplasticity mechanism underlying the effect of AAPs on the impairment of cognitive functions. Here, we treated schizophrenia rat models with a systematic injection of MK-801 (0.1mg/kg) and chose the drug OLZ as a tool to investigate the mechanisms of AAPs when used to alter cognitive function. The results showed that the systematic administration of MK-801 results in the impairment of spatial learning and memory as well as spatial working memory in a Morris water maze task. OLZ but not HAL improved these MK-801-induced cognitive dysfunctions. After MK-801 application, the hippocampal LTP was profoundly impaired. In conjunction with the results of the behavioral test, the administration of OLZ but not of HAL resulted in a significant reversal effect on the impaired LTP induced via MK-801 application. Furthermore, we found that OLZ but not HAL can upregulate the phosphorylation of GluR1 Ser845. These data suggest that the therapeutic effect of OLZ on cognitive dysfunctions may be due to its contribution to synaptic plasticity via the ability to upregulate the state of GluR1 Ser845 phosphorylation. We therefore suggest that the upregulated state of GluR1 Ser845 phosphorylation may be a promising target for developing novel therapeutics for treating schizophrenia.
    Schizophrenia Research 09/2014; 159(2-3). DOI:10.1016/j.schres.2014.07.054 · 3.92 Impact Factor
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    • "Studies have reported both hypoactivation [45], [46] and hyperactivation [47]–[50] of areas of the PFC in patients with schizophrenia. Keshavan et al. [51] reported decreased activity in the dlPFC and inferior PC in offspring of individuals with schizophrenia, while Broome et al. [52] reported decreased activity in the medial PFC and right precuneus in a group of ARMS participants during spatial working memory tasks. "
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    ABSTRACT: Background Deficits in working memory are widely reported in schizophrenia and are considered a trait marker for the disorder. Event-related potentials (ERPs) and imaging data suggest that these differences in working memory performance may be due to aberrant functioning in the prefrontal and parietal cortices. Research suggests that many of the same risk factors for schizophrenia are shared with individuals from the general population who report psychotic symptoms. Methods Forty-two participants (age range 11–13 years) were divided into those who reported psychotic symptoms (N = 17) and those who reported no psychotic symptoms, i.e. the control group (N = 25). Behavioural differences in accuracy and reaction time were explored between the groups as well as electrophysiological correlates of working memory using a Spatial Working Memory Task, which was a variant of the Sternberg paradigm. Specifically, differences in the P300 component were explored across load level (low load and high load), location (positive probe i.e. in the same location as shown in the study stimulus and negative probe i.e. in a different location to the study stimulus) and between groups for the overall P300 timeframe. The effect of load was also explored at early and late timeframes of the P300 component (250-430 ms and 430-750 ms respectively). Results No between-group differences in the behavioural data were observed. Reduced amplitude of the P300 component was observed in the psychotic symptoms group relative to the control group at posterior electrode sites. Amplitude of the P300 component was reduced at high load for the late P300 timeframe at electrode sites Pz and POz. Conclusions These results identify neural correlates of neurocognitive dysfunction associated with population level psychotic symptoms and provide insights into ERP abnormalities associated with the extended psychosis phenotype.
    BMC Psychiatry 05/2013; 13(1):125. DOI:10.1186/1471-244X-13-125 · 2.21 Impact Factor
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