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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: It is proposed that the deactivation failure in the patients' anterior rostral medial prefrontal cortex is related to an increased coupling with the thalamus and reflects a reduced efficiency to flexibly adapt to task demands.

28 citations

Journal ArticleDOI
TL;DR: Higher global band pre-stimulus CS values were associated with worse general cognition in schizophrenia patients and suggest a general hyper-synchronized basal state that might hamper cognition in this syndrome.
Abstract: The application of graph theory measures in the study of functional brain networks allows for the description of their general properties and their alterations in mental illness. Among these measures, connectivity strength (CS) estimates the degree of functional connectivity of the whole network. Previous studies in schizophrenia patients have reported higher baseline CS values and modulation deficits in EEG spectral properties during cognitive activity. The specificity of these alterations and their relationships with pharmacological treatments remain unknown. Therefore, in the present study, we assessed functional CS on EEG-based brain networks in 79 schizophrenia and 29 bipolar patients in addition to 63 healthy controls. The subjects performed a P300 task during the EEG recordings from which the pre-stimulus and the task-related modulation CS values were computed in the global and theta bands. These values were compared between the groups and between the patients who had and had not received different treatments. The global band pre-stimulus CS was significantly higher in the schizophrenia group compared with the bipolar and control groups. Theta band CS modulation was decreased in schizophrenia and bipolar patients. Treatment with antipsychotics, lithium, benzodiazepines, and anticonvulsants did not significantly alter these CS values. The first-episode and chronic schizophrenia patients did not show significant differences in CS values. Higher global band pre-stimulus CS values were associated with worse general cognition in schizophrenia patients. These data support increased connectivity in the whole-brain network that is specific to schizophrenia and suggest a general hyper-synchronized basal state that might hamper cognition in this syndrome.

27 citations

Journal ArticleDOI
TL;DR: The findings point toward an aberrant development of thalamic nuclei and an immature pattern of connectivity with temporal regions in relation to AHs, which might be interpreted as a lack of maturation of thalamocortical connectivity.

27 citations

Journal ArticleDOI
TL;DR: This study confirms previous findings of default hyper-connectivity in schizophrenia spectrum patients and reveals an association between altered default connectivity and positive symptom severity and shows that default connectivity is correlated to and predictive of theory of mind performance.

27 citations


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

  • ...…video clips of facial expressions (Mothersill et al., 2014a), and failure to deactivate the medial prefrontal cortex during other cognitive tasks (e.g. working memory performance) has also been reported in multiple schizophrenia studies (Meyer-Lindenberg et al., 2001; Pomarol-Clotet et al., 2008)....

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  • ...working memory performance) has also been reported in multiple schizophrenia studies (Meyer-Lindenberg et al., 2001; Pomarol-Clotet et al., 2008)....

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Journal ArticleDOI
TL;DR: A putative mechanistic link between connectome topology, hub redistribution, and impaired n-back performance in schizophrenia is demonstrated, which is related to better WM accuracy in patients with more severe negative symptom burden.
Abstract: Background Working memory (WM) deficit is a key feature of schizophrenia that relates to a generalized neural inefficiency of extensive brain areas. To date, it remains unknown how these distributed regions are systemically organized at the connectome level and how the disruption of such organization brings about the WM impairment seen in schizophrenia. Methods We used graph theory to examine the neural efficiency of the functional connectome in different granularity in 155 patients with schizophrenia and 96 healthy controls during a WM task. These analyses were repeated in another independent dataset (81 patients and 54 controls). Linear regression analysis was used to test associations of altered graph properties, clinical symptoms, and WM accuracy in patients. A machine-learning approach was adopted to study the ability of multivariate connectome features from one dataset to discriminate patients from controls in the second dataset. Results Small-worldness of the whole-brain connectome was significantly increased in schizophrenia during the WM task; this increase is related to better (though subpar) WM accuracy in patients with more severe negative symptom burden. There was a shift in the degree distribution to a more homogeneous form in patients. The machine-learning approach classified a new set of patients from controls with 84.3% true-positivity rate for schizophrenia and 71.6% overall accuracy. Conclusions We demonstrate a putative mechanistic link between connectome topology, hub redistribution, and impaired n-back performance in schizophrenia. The task-dependent modulation of the connectome relates to, but remains inefficient in, improving the performance above par in the presence of severe negative symptoms.

26 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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This represented a failure of deactivation in the schizophrenic patients.