Abnormal Functional Activation and Connectivity in the Working Memory Network in Early-Onset Schizophrenia

Institute of Psychiatry, King's College London and Child and Adolescent Mental Health Services, Maudsley Hospital, UK.
Journal of the American Academy of Child and Adolescent Psychiatry (Impact Factor: 7.26). 09/2012; 51(9):911-20.e2. DOI: 10.1016/j.jaac.2012.06.020
Source: PubMed


Disruption within the working memory (WM) neural network is considered an integral feature of schizophrenia. The WM network, and the dorsolateral prefrontal cortex (DLPFC) in particular, undergo significant remodeling in late adolescence. Potential interactions between developmental changes in the WM network and disease-related processes for schizophrenia remain unclear. The aim of this study was to determine whether DLPFC activation and functional connectivity are impaired during WM in patients with early-onset schizophrenia (EOS; age of onset <18 years).
We used functional magnetic resonance imaging and psychophysiological interaction analysis to respectively measure blood oxygenation level-dependent signal and to derive functional connectivity estimates in response to the two-back WM task from 25 youths with EOS and 20 matched healthy adolescents.
Compared with healthy adolescents, patients with EOS showed reduced engagement of the DLPFC, the anterior cingulate cortex (ACC), and frontal operculum, and had reduced DLPFC connectivity within the WM network. Patients with EOS showed abnormal reduction in the coupling of the DLPFC with the ACC, the inferior parietal lobule, and the middle occipital gyrus. In contrast to healthy adolescents, patients with EOS expressed age-related decrease in the activity of the DLPFC and an increase in its connectivity with the ACC.
Patients with EOS show dysfunctional engagement and reduced integration within the WM neural network. The pattern of abnormal age-related correlations in DLPFC activity and connectivity suggests that schizophrenia-related processes have an impact on brain regions that show significant late developmental changes.


Available from: Jonathan Roiser, Jun 03, 2015
    • "Furthermore, in early-onset schizophrenia patients (<18 years old), fMRI shows reduced blood oxygenation level-dependent signals in the Work-Mem network, which comprises the dorsolateral prefrontal cortex (DLPFC), frontal operculum and anterior cingulate cortex (ACC) (Kyriakopoulos et al. 2012). Disruption of normal remodeling of the Work-Mem network in adolescence may cause the impairment seen in future adult cases of schizophrenia; however, the exact leading mechanisms are unknown (Kyriakopoulos et al. 2012). Abnormalities of the ACC, a key component of the Work- Mem network, are strongly associated with schizophrenia (Bush et al. 2000; Fornito et al. 2009). "
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    ABSTRACT: Working memory (Work-Mem), the capacity to hold and manipulate information, activates the anterior cingulate cortex (ACC), especially its caudal subregion. Impaired Work-Mem and structural and functional abnormalities of the ACC are reported in schizophrenia. This study aims to elucidate the pathogenesis of Work-Mem dysfunction in schizophrenia by comparing metabolite concentrations across ACC subregions. This retrospective study of 18 schizophrenia cases and 10 matched controls used proton magnetic resonance spectroscopic imaging ((1)H-MRSI, TR/TE = 1800/35 ms, 0.5 cm(3) spatial resolution) to test whether the Work-Mem Index of the Wechsler Adult Intelligence Scale, third edition is associated with differences in the rostral to caudal ACC ratios of N-acetylaspartate (NAA) and creatine (Cr). Higher caudal:rostral ACC Cr (but not NAA) concentrations were associated with decreased Work-Mem Index in cases (r = -0.6, p = 0.02), with a similar trend in controls (r = -0.56, p = 0.10), although caudal:rostral ACC Cr correlated with NAA in cases and controls (r = 0.67 and 0.62, p < 0.05 for both). NAA and Cr ratios did not correlate with myo-inositol, excluding gliosis as the underlying process. Subjects' sex and age had no effects on these relationships. The findings suggest that rostral ACC energy hypo-metabolism, possibly arising from neurodevelopmental processes, is associated with working memory impairment in schizophrenia. Changes in the rostral (not the expected caudal) subregion underscore the interconnections between the ACC subregions and may offer laboratory markers for treatment trials, etiology studies, and perhaps even enhanced identification of prodromal "at risk" subjects.
    Brain Imaging and Behavior 03/2015; DOI:10.1007/s11682-015-9372-x · 4.60 Impact Factor
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    • "This connection may prove quite important, as earlier reports found that early age at onset of schizophrenia is correlated with prominent deficits in executive functioning [Holmen et al., 2010; Jepsen et al., 2010]. Similarly, the dorsolateral prefrontal cortex (DLPFC) has been shown to undergo evolution in executive functioning in adolescence [Gogtay et al., 2004], and abnormalities of DLPFC have reliably been shown to be associated with schizophrenia [Kyriakopoulos et al., 2012]. Taking these results alongside those of the present study, the role of rs1800497 polymorphism in age at onset of schizophrenia may then lay in its regulatory effect on D2 receptor in DLPFC. "
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    ABSTRACT: One functional polymorphism (rs1800497) within the ankyrin repeat and kinase domain containing-1 gene (ANKK1) was reported to be associated with schizophrenia, but results among different studies vary and conclusions remain controversial. The present study sought to clarify this potential association among a population of Han Chinese with early onset schizophrenia using a case-control (396 patients and 399 controls) and family based study (103 trios). We then performed a meta-analysis (comprising 11 case-control and 2 family-based studies) based on the present literature. Results of the association study revealed no significant difference in allele and genotype frequencies between the cases and controls, and no significant transmission distortion was detected. Kaplan–Meier survival analysis showed that age at onset in schizophrenia was significantly associated with the rs1800497 polymorphism in female patients, but not in males. Female T allele carriers had a lower age at onset than those without T allele (log rank statistic χ2 = 5.16, P = 0.023; corrected P = 0.046). Meta-analysis results indicated that rs1800497 is not associated with schizophrenia in the overall population (P = 0.77 for the case-control studies; P = 0.06 for the family-based studies). Our results support the hypothesis that rs1800497 polymorphism is likely to have a modifying rather than causative effect on schizophrenia. These findings may represent a significant genetic clue for the etiology of schizophrenia in females, but further investigation is required to clarify the exact role of ANKK1 in the development of schizophrenia. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2014; 165(7). DOI:10.1002/ajmg.b.32259 · 3.42 Impact Factor
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    • "In psychiatric diseases such as SZ, the ACC is affected and its activation often abnormal (Dolan et al., 1995; Minzenberg et al., 2009; Kyriakopoulos et al., 2012). Specifically, attention executive function, decision making and cost benefit analysis that all require the ACC are impaired in patients. "
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    ABSTRACT: Dopamine release in the prefrontal cortex plays a critical role in cognitive function such as working memory, attention and planning. Dopamine exerts complex modulation on excitability of pyramidal neurons and interneurons, and regulates excitatory and inhibitory synaptic transmission. Because of the complexity of this modulation, it is difficult to fully comprehend the effect of dopamine on neuronal network activity. In this study, we investigated the effect of dopamine on local high-frequency oscillatory neuronal activity (in β band) in slices of the mouse anterior cingulate cortex (ACC). We found that dopamine enhanced the power of these oscillations induced by kainate and carbachol, but did not affect their peak frequency. Activation of D2R and in a lesser degree D1R increased the oscillation power, while activation of D4R had no effect. These high-frequency oscillations in the ACC relied on both phasic inhibitory and excitatory transmission and functional gap junctions. Thus, dopamine released in the ACC promotes high-frequency synchronized local cortical activity which is known to favor information transfer, fast selection and binding of distributed neuronal responses. Finally, the power of these oscillations was significantly enhanced after degradation of the perineuronal nets (PNNs) enwrapping most parvalbumin interneurons. This study provides new insights for a better understanding of the abnormal prefrontal gamma activity in schizophrenia (SZ) patients who display prefrontal anomalies of both the dopaminergic system and the PNNs.
    Frontiers in Cellular Neuroscience 08/2014; 8:244. DOI:10.3389/fncel.2014.00244 · 4.29 Impact Factor
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