Working memory and DLPFC inefficiency in schizophrenia: The FBIRN study

Potkin, Steven G.; Turner, Jessica A.; Brown, Greg; McCarthy, Gregory; Greve, Doug; Glover, Gary H.; Manoach, Dara S.; Belger, Ayşenil; Diaz, Michèle T.; Wible, Cynthia G.; Ford, J.M.; Mathalon, Daniel H.; Gollub, Randy L.; Lauriello, John; O'Leary, Daniel S.; Erp, Theo G.M. van; Toga, Arthur W.; Preda, Adrian; Lim, Kelvin O.

doi:10.1093/schbul/sbn162

Cited by 306 publications

(289 citation statements)

References 63 publications

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“…Healthy controls had a mean verbal IQ of 110 (SD, Ϯ10.50) and a mean of 15 years of education (SD, Ϯ3.70). As in previous studies, verbal IQ was significantly higher in healthy controls, as were years of education (Potkin et al, 2009;Morris et al, 2011).…”

Section: Participants and Instrumentssupporting

confidence: 85%

Reduced Prefrontal-Parietal Effective Connectivity and Working Memory Deficits in Schizophrenia

et al. 2012

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The neural mechanisms behind cognitive deficits in schizophrenia still remain unclear. Functional neuroimaging studies on working memory (WM) yielded inconsistent results, suggesting task performance as a moderating variable of prefrontal activation. Beyond regional specific activation, disordered integration of brain regions was supposed as a critical pathophysiological mechanism of cognitive deficits in schizophrenia. Here, we first hypothesized that prefrontal activation implicated in WM depends primarily on task performance and therefore stratified participants into performance subgroups. Second, in line with the dysconnectivity hypothesis, we asked whether connectivity in the prefrontal-parietal network underlying WM is altered in all patients. We used functional magnetic resonance imaging in human subjects (41 schizophrenia patients, 42 healthy controls) and dynamic causal modeling to examine effective connectivity during a WM task. In line with our first hypothesis, we found that prefrontal activation was differentially modulated by task performance: there was a significant task by group by performance interaction revealing an increase of activation with performance in patients and a decrease with performance in controls. Beyond that, we show for the first time that WM-dependent effective connectivity from prefrontal to parietal cortex is reduced in all schizophrenia patients. This finding was independent of performance. In conclusion, our results are in line with the highly influential hypothesis that the relationship between WM performance and prefrontal activation follows an inverted U-shaped function. Moreover, this study in a large sample of patients reveals a mechanism underlying prefrontal inefficiency and cognitive deficits in schizophrenia, thereby providing direct experimental evidence for the dysconnectivity hypothesis.

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Section: Participants and Instrumentssupporting

confidence: 85%

Reduced Prefrontal-Parietal Effective Connectivity and Working Memory Deficits in Schizophrenia

et al. 2012

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“…[4][5][6][7][8][9][10]44,45 Part of the importance of the present investigation is that it shows that frontal functional connectivity changes involving the inferior frontal gyrus are present in FE, antipsychoticnaive patients. A recent review 2 of functional connectivity changes in schizophrenia involved typically much smaller sample sizes than those reported here, and reported typically altered functional connectivity in patients sometimes involving the frontal lobe, but without much emphasis on the thalamus, and with no marked stage-specific differences in functional connectivity.…”

Section: Discussionmentioning

confidence: 99%

“…The pathophysiology of schizophrenia involves distributed functional dysconnectivity involving a number of brain regions, 1,2 including the frontal lobe, [3][4][5][6][7][8][9][10] and its language-related areas in the inferior frontal gyrus, 11,12 sensory-motor areas, 13 the temporal lobe, 14 limbic structures, 15,16 and thalamus. [17][18][19][20][21][22][23][24] Despite numerous leads, the reported findings are somewhat inconsistent and the core regions associated with the pathogenesis of schizophrenia still remain controversial.…”

Section: Introductionmentioning

confidence: 99%

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia

Wang

Zhang

et al. 2016

SCHBUL

144

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Published reports of functional abnormalities in schizophrenia remain divergent due to lack of staging point-of-view and whole-brain analysis. To identify key functional-connectivity differences of first-episode (FE) and chronic patients from controls using resting-state functional MRI, and determine changes that are specifically associated with disease onset, a clinical staging model is adopted. We analyze functionalconnectivity differences in prodromal, FE (mostly drug naïve), and chronic patients from their matched controls from 6 independent datasets involving a total of 789 participants (343 patients). Brain-wide functional-connectivity analysis was performed in different datasets and the results from the datasets of the same stage were then integrated by meta-analysis, with Bonferroni correction for multiple comparisons. Prodromal patients differed from controls in their pattern of functionalconnectivity involving the inferior frontal gyri (Broca's area). In FE patients, 90% of the functional-connectivity changes involved the frontal lobes, mostly the inferior frontal gyrus including Broca's area, and these changes were correlated with delusions/blunted affect. For chronic patients, functionalconnectivity differences extended to wider areas of the brain, including reduced thalamo-frontal connectivity, and increased thalamo-temporal and thalamo-sensorimoter connectivity that were correlated with the positive, negative, and general symptoms, respectively. Thalamic changes became prominent at the chronic stage. These results provide evidence for distinct patterns of functional-dysconnectivity across FE and chronic stages of schizophrenia. Importantly, abnormalities in the frontal language networks appear early, at the time of disease onset. The identification of stage-specific pathological processes may help to understand the disease course of schizophrenia and identify neurobiological markers crucial for early diagnosis.

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“…Impaired WM is a well-documented symptom in schizophrenia and arguably a core feature of the disease. Many studies investigating WM deficits in schizophrenia focus on the dorsolateral prefrontal cortex (dlPFC), a region implicated in executive functions, goal-directed planning, and inhibition (Jansma et al, 2004;Manoach et al, 2000;Potkin et al, 2009). However, the direction of dlPFC findings has been inconsistent across studies, which have demonstrated both diminished and enhanced dlPFC activation in schizophrenia (Carter et al, 1998;Manoach et al, 1999;Potkin et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, WM function depends not only on activation of dlPFC and other nodes within the frontoparietal control network (FPCN) but also on deactivation of the default mode network (DMN; Anticevic et al, 2010). Numerous recent studies have identified altered DMN activation and connectivity in schizophrenia (Kim et al, 2009;Meda et al, 2009), complementing a large volume of work implicating FPCN dysfunction (Karlsgodt et al, 2007;Manoach et al, 2000;Minzenberg et al, 2009;Potkin et al, 2009). However, the relationship between WM deficits and both task-related activation and intrinsic network connectivity remains incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Disrupted Working Memory Circuitry in Schizophrenia: Disentangling fMRI Markers of Core Pathology vs Other Aspects of Impaired Performance

Eryilmaz

Tanner

et al. 2016

Neuropsychopharmacol

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Working memory (WM) impairment, a core feature of schizophrenia, is often associated with aberrant dorsolateral prefrontal cortex (dlPFC) activation. Reduced resting-state connectivity within the frontoparietal control network (FPCN) has also been reported in schizophrenia. However, interpretation of WM-related dlPFC dysfunction has been limited by performance differences between patients and controls, and by uncertainty over the relevance of resting-state connectivity to network engagement during task. We contrasted brain activation in 40 schizophrenia patients and 40 controls during verbal WM performance, and evaluated underlying functional connectivity during rest and task. During correct trials, patients demonstrated normal FPCN activation, despite an inverse relationship between positive symptoms and activation. FPCN activation differed between the groups only during error trials (controls4patients). In contrast, controls demonstrated stronger deactivation of the ventromedial prefrontal cortex (vmPFC) during correct and error trials. Functional connectivity analysis indicated impaired resting-state FPCN connectivity in patients, but normal connectivity during task. However, patients showed abnormal connectivity among regions such as vmPFC, lateral orbitofrontal cortex, and parahippocampal gyrus (PHG) during both rest and task. During task, patients also exhibited altered thalamic connectivity to PHG and FPCN. Activation and connectivity patterns that were more characteristic of controls generally correlated with better performance. In summary, patients demonstrated normal FPCN activation when they remained on-task, and exhibited normal FPCN connectivity during WM, whereas vmPFC deactivation differences persisted regardless of WM performance. Our findings suggest that altered FPCN activation in patients reflects performance difference, and that limbic and thalamic dysfunction is critically involved in WM deficits in schizophrenia.

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Working memory and DLPFC inefficiency in schizophrenia: The FBIRN study

Cited by 306 publications

References 63 publications

Reduced Prefrontal-Parietal Effective Connectivity and Working Memory Deficits in Schizophrenia

Reduced Prefrontal-Parietal Effective Connectivity and Working Memory Deficits in Schizophrenia

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia

Disrupted Working Memory Circuitry in Schizophrenia: Disentangling fMRI Markers of Core Pathology vs Other Aspects of Impaired Performance

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