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Journal ArticleDOI

Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network?

TL;DR: Patients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task, including an area in the anterior prefrontal/anterior cingulate cortex that corresponds to one of the two midline components of the ‘default mode network’ implicated in functions related to maintaining one's sense of self.
Abstract: BackgroundFunctional imaging studies using working memory tasks have documented both prefrontal cortex (PFC) hypo- and hyperactivation in schizophrenia. However, these studies have often failed to consider the potential role of task-related deactivation.MethodThirty-two patients with chronic schizophrenia and 32 age- and sex-matched normal controls underwent functional magnetic resonance imaging (fMRI) scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups.ResultsThe controls showed activation in the expected frontal regions. There were also clusters of deactivation, particularly in the anterior cingulate/ventromedial PFC and the posterior cingulate cortex/precuneus. Compared to the controls, the schizophrenic patients showed reduced activation in the right dorsolateral prefrontal cortex (DLPFC) and other frontal areas. There was also an area in the anterior cingulate/ventromedial PFC where the patients showed apparently greater activation than the controls. This represented a failure of deactivation in the schizophrenic patients. Failure to activate was a function of the patients' impaired performance on the n-back task, whereas the failure to deactivate was less performance dependent.ConclusionsPatients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task. The area of failure of deactivation is in the anterior prefrontal/anterior cingulate cortex and corresponds to one of the two midline components of the ‘default mode network’ implicated in functions related to maintaining one's sense of self.
Citations
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Journal ArticleDOI
TL;DR: This method proved superior to the standard means of correction whereby realignment parameters and their first order derivatives are used as covariates of no interest in a linear regression model.

11 citations


Cites background from "Failure to deactivate in the prefro..."

  • ...…in the DMN have been observed in rzbauer@abdn.ac.uk rights reserved. many neurological disorders, including Alzheimer's disease (Greicius et al., 2004; He et al., 2007), depression (Greicius et al., 2007; Sheline et al., 2010) and schizophrenia (Liang et al., 2006; Pomarol-Clotet et al., 2008)....

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Journal ArticleDOI
TL;DR: Results support the transdiagnostic nature of behavioral and neuroimaging measures of emotion-related WM disruption as they relate to psychotic symptoms, irrespective of diagnosis and provide support for the practical utility of these markers in explaining real-world functioning.
Abstract: Deficits in working memory (WM) and emotion processing are prominent impairments in psychotic disorders, and have been linked to reduced quality of life and real-world functioning. Translation of knowledge regarding the neural circuitry implementing these deficits into improved diagnosis and targeted treatments has been slow, possibly because of categorical definitions of disorders. Using the dimensional Research Domain Criteria (RDoC) framework, we investigated the clinical and practical utility of transdiagnostic behavioral and neural measures of emotion-related WM disruption across psychotic disorders. Behavioral and functional MRI data were recorded while 53 participants with psychotic disorders and 29 participants with no history of psychosis performed a modified n-back task with fear and neutral distractors. Hierarchical regression analyses showed that psychotic symptoms entered after diagnosis accounted for unique variance in fear versus neutral accuracy and activation in the ventrolateral, dorsolateral, and dorsomedial prefrontal cortex, but diagnostic group entered after psychotic symptoms did not. These results remained even after controlling for negative symptoms, disorganized symptoms, and dysphoria. Finally, worse accuracy and greater prefrontal activity were associated with poorer social functioning and unemployment across diagnostic groups. Present results support the transdiagnostic nature of behavioral and neuroimaging measures of emotion-related WM disruption as they relate to psychotic symptoms, irrespective of diagnosis. They also provide support for the practical utility of these markers in explaining real-world functioning. Overall, these results elucidate key aspects of the RDoC construct of WM maintenance by clarifying its transdiagnostic importance and clinical utility in psychotic disorders. (PsycINFO Database Record

11 citations


Cites background or methods from "Failure to deactivate in the prefro..."

  • ...Using the n-back task, several studies have reported greater activation of the DMPFC in individuals with schizophrenia relative to controls (Pomarol-Clotet et al., 2008, 2010; Whitfield-Gabrieli et al., 2009)....

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  • ...Moreover, positive and negative symptoms in schizophrenia have been found to be positively correlated with higher activity in the DMPFC during WM performance (Pomarol-Clotet et al., 2008)....

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Journal ArticleDOI
TL;DR: Findings suggest that inability to suppress irrelevant internally-generated information while processing external stimuli might be the basis of functional psychopathology in schizophrenia.

11 citations


Cites background from "Failure to deactivate in the prefro..."

  • ...A failure of mPFC task-related deactivation has been recently presented in schizophrenia (Pomarol-Clotet et al., 2008; WhitfieldGabrieli et al., 2009; Guerrero-Pedraza et al., 2012)....

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Journal ArticleDOI
TL;DR: Standard accounts of delusion make sense to retain that aspect of the standard account in the face of revisionist arguments that feature binding anomalies which lead to delusions of misidentification are not consciously experienced.

10 citations

Journal ArticleDOI
TL;DR: The authors start with the role of dopamine dysregulation which is believed to contribute to the pathogenesis of schizophrenia, and hypothesize that the hippocampus and nucleus accumbens are potential targets for deep brain stimulation in the treatment of this disease.
Abstract: Most troubling, however, may be that schizophrenia is a group of syndromes in which the physiologic derangements differ rather than a solitary disease in and of itself [7] . Thus, stimulation of a target which only affects the dopamine system may only treat some of the symptoms of schizophrenia, likely the positive symptoms and do little for the ‘negative and cognitive symptoms’. As the authors have alluded, this may still be a worthwhile goal. To be successful it is not imperative that all symptoms improve but that the patient’s overall quality of life be enhanced. This may be achieved by diminishing the amount and number of drugs, and improving drug performance among others. At worst, however, partial treatment of schizophrenia by modulating the dopamine system may lead to unintended effects previously unanticipated. As such, this review article must be regarded as highly preliminary that requires more basic research before transition to clinical study. Multiple leads in numerous targets may be required to treat all the symptoms of schizophrenia [2] . Even with this in mind, however, the authors have presented a very interesting argument for the future role of deep brain stimulation in this disorder. Thus, it could represent a small step toward effective palliation of this disease. Undeniably, schizophrenia is a chronic life-altering disorder of the brain that merits vigorous investigation. In this review article, Mikell et al. [1] discuss the hypothetical use of deep brain stimulation in the hippocampus or nucleus accumbens to treat schizophrenia. From a historical prospective there is a modest literature on the nucleus accumbens or ‘septal area’ by direct or indirect lesioning or stimulation. Hallucinations, delusions, depression, anxiety, aggression, obsessions and ‘schizoaffective’ disorders (generally referring to manic depression, but all of these terms used might be defined differently today) were reportedly helped by medial thalamotomy, amygdalotomy, hypothalamotomy, anterior cingulotomy, corpus callosotomy and multiple lesion combinations. Schizophrenia is a very diffuse disorder and the ‘triple target’ lesioning of Cox and Brown [2] was an attempt to include key areas believed to be affected. But in the most extensive review of this literature by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1977 [3] , schizophrenia was the least likely disorder to improve. The hippocampus would be a totally novel target for schizophrenia. In this era, we should be striving for reestablishment of emotional control while preserving cognition and personality without blunting affect. They start with the role of dopamine dysregulation which is believed to contribute to the pathogenesis of schizophrenia. They then go on to hypothesize that the hippocampus and nucleus accumbens are potential targets for deep brain stimulation in the treatment of this disease. While the authors should be commended for the intriguing discussion of the possibility of deep brain stimulation for this dreaded syndrome for which current treatments are still unsatisfactory, it should be regarded with caution. The neurophysiologic and neuroanatomic basis of schizophrenia has to this time not been well elucidated. While most agree that dopamine dysregulation plays an important part in the development of the positive symptoms of schizophrenia such as hallucinations and psychosis, it is probable that the neurotransmitter derangements are more wide-ranging than simply dopamine dysregulation. Current treatment of schizophrenia includes the use of atypical antipsychotics, which affect serotonin in addition to dopamine, in contrast to typical antipsychotics. This suggests that serotonin may play an important role as well [4] . In addition, recent studies have suggested that glutamate dysregulation may also have a critical responsibility in the pathogenesis of schizophrenia [5] . Also, recent studies have even suggested an autoimmune basis for the development of schizophrenia [6] . Published online: June 26, 2009

10 citations

References
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Journal ArticleDOI
TL;DR: A review of the research carried out by the Analysis Group at the Oxford Centre for Functional MRI of the Brain (FMRIB) on the development of new methodologies for the analysis of both structural and functional magnetic resonance imaging data.

12,097 citations

Book
01 Jan 1966
TL;DR: This book discusses statistical decision theory and sensory processes in signal detection theory and psychophysics and describes how these processes affect decision-making.
Abstract: Book on statistical decision theory and sensory processes in signal detection theory and psychophysics

11,820 citations


"Failure to deactivate in the prefro..." refers methods in this paper

  • ...The behavioural measure used was the signal detection theory index of sensitivity, dk (Green & Swets, 1966)....

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Journal ArticleDOI
TL;DR: A baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF is identified, suggesting the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.
Abstract: A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed). Local deviations in the OEF represent the physiological basis of signals of changes in neuronal activity obtained with functional MRI during a wide variety of human behaviors. We used quantitative metabolic and circulatory measurements from positron-emission tomography to obtain the OEF regionally throughout the brain. Areas of activation were conspicuous by their absence. All significant deviations from the mean hemisphere OEF were increases, signifying deactivations, and resided almost exclusively in the visual system. Defining the baseline state of an area in this manner attaches meaning to a group of areas that consistently exhibit decreases from this baseline, during a wide variety of goal-directed behaviors monitored with positron-emission tomography and functional MRI. These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.

10,708 citations


"Failure to deactivate in the prefro..." refers background or result in this paper

  • ...This interpretation is supported by (a) the spatial correspondence between this area and that identified in studies of the default mode network (e.g. Gusnard et al. 2001 ; Raichle et al. 2001), and (b) the fact that the controls in our study showed deactivation in the same area while performing the n-back task....

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  • ...the inferior parietal cortex and parts of the temporal lobe including the hippocampus), these are thought to constitute a ‘default mode network’ that is active at rest or when engaging in ‘stimulus-independent’ thought, but which undergoes a reduction in activity when attentiondemanding goal-directed cognition needs to be undertaken (Gusnard et al. 2001 ; Raichle et al. 2001 ; Greicius et al. 2003 ; Gusnard, 2005)....

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  • ...…is supported by (a) the spatial correspondence between this area and that identified in studies of the default mode network (e.g. Gusnard et al. 2001 ; Raichle et al. 2001), and (b) the fact that the controls in our study showed deactivation in the same area while performing the n-back task....

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  • ...…a ‘default mode network’ that is active at rest or when engaging in ‘stimulus-independent’ thought, but which undergoes a reduction in activity when attentiondemanding goal-directed cognition needs to be undertaken (Gusnard et al. 2001 ; Raichle et al. 2001 ; Greicius et al. 2003 ; Gusnard, 2005)....

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Journal ArticleDOI
TL;DR: This study constitutes, to the knowledge, the first resting-state connectivity analysis of the default mode and provides the most compelling evidence to date for the existence of a cohesive default mode network.
Abstract: Functional imaging studies have shown that certain brain regions, including posterior cingulate cortex (PCC) and ventral anterior cingulate cortex (vACC), consistently show greater activity during resting states than during cognitive tasks. This finding led to the hypothesis that these regions constitute a network supporting a default mode of brain function. In this study, we investigate three questions pertaining to this hypothesis: Does such a resting-state network exist in the human brain? Is it modulated during simple sensory processing? How is it modulated during cognitive processing? To address these questions, we defined PCC and vACC regions that showed decreased activity during a cognitive (working memory) task, then examined their functional connectivity during rest. PCC was strongly coupled with vACC and several other brain regions implicated in the default mode network. Next, we examined the functional connectivity of PCC and vACC during a visual processing task and show that the resultant connectivity maps are virtually identical to those obtained during rest. Last, we defined three lateral prefrontal regions showing increased activity during the cognitive task and examined their resting-state connectivity. We report significant inverse correlations among all three lateral prefrontal regions and PCC, suggesting a mechanism for attenuation of default mode network activity during cognitive processing. This study constitutes, to our knowledge, the first resting-state connectivity analysis of the default mode and provides the most compelling evidence to date for the existence of a cohesive default mode network. Our findings also provide insight into how this network is modulated by task demands and what functions it might subserve.

6,025 citations


"Failure to deactivate in the prefro..." refers background in this paper

  • ...the inferior parietal cortex and parts of the temporal lobe including the hippocampus), these are thought to constitute a ‘default mode network’ that is active at rest or when engaging in ‘stimulus-independent’ thought, but which undergoes a reduction in activity when attentiondemanding goal-directed cognition needs to be undertaken (Gusnard et al. 2001 ; Raichle et al. 2001 ; Greicius et al. 2003 ; Gusnard, 2005)....

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  • ...…a ‘default mode network’ that is active at rest or when engaging in ‘stimulus-independent’ thought, but which undergoes a reduction in activity when attentiondemanding goal-directed cognition needs to be undertaken (Gusnard et al. 2001 ; Raichle et al. 2001 ; Greicius et al. 2003 ; Gusnard, 2005)....

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Journal ArticleDOI
TL;DR: This work explores the possibility that there might be a baseline or resting state of brain function involving a specific set of mental operations, including the manner in which a baseline is defined and the implications of such a baseline for the understanding ofbrain function.
Abstract: Functional brain imaging in humans has revealed task-specific increases in brain activity that are associated with various mental activities. In the same studies, mysterious, task-independent decreases have also frequently been encountered, especially when the tasks of interest have been compared with a passive state, such as simple fixation or eyes closed. These decreases have raised the possibility that there might be a baseline or resting state of brain function involving a specific set of mental operations. We explore this possibility, including the manner in which we might define a baseline and the implications of such a baseline for our understanding of brain function.

3,285 citations


"Failure to deactivate in the prefro..." refers background or result in this paper

  • ...Two studies, however, had opposite results to ours : Harrison et al. (2007) found that 12 schizophrenic patients showed greater deactivation of both the anterior and posterior cingulate midline loci than in 14 controls during a task requiring response suppression. Using an auditory oddball task, Garrity et al. (2007) found that 21 patients with schizophrenia showed a complex pattern of abnormality compared to 22 normal controls, but deactivation was increased in the anterior cingulate/ superior medial frontal gyri. The remaining two studies (Bluhm et al. 2007 ; Zhou et al. 2007) focused exclusively on connectivity, and cannot be directly compared with our findings. Of note, Kennedy et al. (2006) have also documented default mode network dysfunction in adult high-functioning autisticspectrum patients, although they found that the failure of deactivation affected both the anterior and posterior midline loci of the network....

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  • ...Gusnard et al. 2001 ; Raichle et al. 2001), and (b) the fact that the controls in our study showed deactivation in the same area while performing the n-back task. Menzies et al. (2007) also interpreted the failure to deactivate they found in schizophrenia in terms of default mode network dysfunction. However, as neither we nor Menzies et al. (2007) set out specifically to examine default mode network function in schizophrenia, such an interpretation should be regarded as provisional....

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  • ...Two studies, however, had opposite results to ours : Harrison et al. (2007) found that 12 schizophrenic patients showed greater deactivation of both the anterior and posterior cingulate midline loci than in 14 controls during a task requiring response suppression. Using an auditory oddball task, Garrity et al. (2007) found that 21 patients with schizophrenia showed a complex pattern of abnormality compared to 22 normal controls, but deactivation was increased in the anterior cingulate/ superior medial frontal gyri....

    [...]

  • ...the inferior parietal cortex and parts of the temporal lobe including the hippocampus), these are thought to constitute a ‘default mode network’ that is active at rest or when engaging in ‘stimulus-independent’ thought, but which undergoes a reduction in activity when attentiondemanding goal-directed cognition needs to be undertaken (Gusnard et al. 2001 ; Raichle et al. 2001 ; Greicius et al. 2003 ; Gusnard, 2005)....

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  • ...Gusnard et al. (2001) have also reviewed various lines of evidence that suggest that different parts of the default mode network are involved in gathering information about the world, orienting oneself to salient environmental stimuli, theory of mind and self-representation....

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How long can a schizophrenic go without sleep?

This represented a failure of deactivation in the schizophrenic patients.