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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: Comparing cerebral perfusion using single-photon emission tomography (SPECT) in patients and controls to study the association between activation patterns and cognitive performance in this disease found patients with paranoid schizophrenia showed an increased perfusion in the right hippocampus with respect to healthy controls, they also displayed a statistically significant inverse association between perfusions in the left hippocampus and verbal memory performance.

6 citations


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

  • ...The smaller amount of deactivation deficit in patients with schizophrenia in comparison to healthy controls (Pomarol-Clotet et al., 2008; Whitfield-Gabrieli et al., 2009) could contribute to the globally worse performance in the former....

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  • ...This seems coherent with the lessened deactivation of the default mode network (DMN) reported in schizophrenia in comparison to healthy participants (Ongur et al., 2010; Pomarol-Clotet et al., 2008)....

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Journal ArticleDOI
TL;DR: In this paper, the authors investigated the neurobiological mechanisms underlying the preparation function of the cortisol awakening response (CAR) across two studies and established a causal link between the CAR and its proactive role in optimizing functional brain networks involved in neuroendocrine control, executive function and memory.

6 citations

Journal ArticleDOI
TL;DR: Results suggest a mechanism by which faulty DMN deactivation, a hallmark of pathological findings in SZ, is achieved, and high Glx in unmedicated patients predicted less deactivation of the DMN.
Abstract: There is no pharmacological treatment to remediate cognitive impairment in schizophrenia (SZ). It is imperative to characterize underlying pathologies of memory processing in order to effectively develop new treatments. In this longitudinal study, we combined functional magnetic resonance imaging during a memory encoding task with proton MR spectroscopy to measure hippocampal glutamate + glutamine (Glx). Seventeen SZ were scanned while unmedicated and after 6 weeks of treatment with risperidone and compared to a group of matched healthy controls (HC) scanned 6 weeks apart. Unmedicated patients showed reduced blood oxygen level dependent (BOLD) response in several regions, including the hippocampus, and greater BOLD response in regions of the default mode network (DMN) during correct memory encoding. Post hoc contrasts from significant group by time interactions indicated reduced hippocampal BOLD response at baseline with subsequent increase following treatment. Hippocampal Glx was not different between groups at baseline, but at week 6, hippocampal Glx was significantly lower in SZ compared to HC. Finally, in unmedicated SZ, higher hippocampal Glx predicted less deactivation of the BOLD response in regions of the DMN. Using 2 brain imaging modalities allowed us to concurrently investigate different mechanisms involved in memory encoding dysfunction in SZ. Hippocampal pathology during memory encoding stems from decreased hippocampal recruitment and faulty deactivation of the DMN, and hippocampal recruitment during encoding can be modulated by antipsychotic treatment. High Glx in unmedicated patients predicted less deactivation of the DMN; these results suggest a mechanism by which faulty DMN deactivation, a hallmark of pathological findings in SZ, is achieved.

5 citations

Dissertation
14 Jul 2017
TL;DR: In this article, the razonamiento contrafactual (RC) model is used to evaluate the effect of interventions on the performance of the RC model in the context of cognitive deficits.
Abstract: La esquizofrenia es un trastorno grave y de etiologia multifactorial. Actualmente, existe un consenso general de que los deficits neurocognitivos son una caracteristica nuclear de la esquizofrenia. Para ello, extensas lineas de investigacion se han centrado en la identificacion de deficits cognitivos similares en familiares no afectados de pacientes con esquizofrenia que podrian ser considerados como posibles endofenotipos cognitivos de la enfermedad. El razonamiento contrafactual (RC) es un tipo especifico de razonamiento condicional relacionado con la generacion de simulaciones mentales de acontecimientos pasados que facilita la conducta adaptativa asi como la toma de decisiones dirigida a un objetivo. Las investigaciones preliminares realizadas hasta la fecha evidencian un deterioro del RC en la esquizofrenia, lo cual podria suponer un importante impacto en el funcionamiento diario de estos pacientes. A la luz de estos resultados, investigadores en este campo refuerzan la importancia de continuar estudiando el RC en la esquizofrenia ya que en el futuro podria suponer el desarrollo de una nueva herramienta de diagnostico o incluso una nueva diana terapeutica. OBJETIVOS: La presente tesis tiene como objetivo profundizar en la caracterizacion de los deficits de RC en pacientes con esquizofrenia y en familiares de primer grado no psicoticos en comparacion con sujetos controles sanos. En un compendio de 4 estudios, diferentes medidas de RC se han evaluado en esta tesis incluyendo: (1) la activacion espontanea de pensamientos contrafactuales, (2) la generacion de inferencias contrafactuales, (3) el efecto de facilitador del RC en la activacion de intenciones conductuales previas a la implementacion de nuevas conductas. RESULTADOS: En el primer estudio evaluamos 40 pacientes con esquizofrenia y 40 controles. Los analisis evidenciaron en los pacientes un empobrecimiento en la capacidad de generar alternativas contrafactuales, asi como una desviacion en el patron de inferencias contrafactuales. En el segundo estudio evaluamos las mismas medidas contrafactuales pero en 78 pacientes cumpliendo criterios de remision sintomatica (Andreasen et al., 2005) en comparacion con un grupo de 84 controles; los resultados no solo evidenciaron las mismas dificultades en los pacientes, sino que encontramos asociaciones negativas significativas entre menor numero de pensamientos contrafactuales generados y (i) nivel de gravedad de los sintomas (PANSS) y (ii) mayor anos de duracion de la enfermedad (>10 anos). En el tercer estudio evaluamos las mismas medidas de RC que en los dos estudios anteriores esta vez en 43 familiares de primer grado no psicoticos, 54 pacientes con esquizofrenia en estado de remision y 44 controles sanos. Los resultados sugirieron un deficit entre los familiares puesto que presentaron patron de respuesta similar a los de los pacientes con esquizofrenia y no al de los sujetos controles. Finalmente, en el estudio 4 evaluamos la capacidad de generar intenciones conductuales a partir de la inferencia contrafactual utilizando una tarea de facilitacion semantica en un grupo de 37 pacientes con esquizofrenia y 37 controles sanos. Los resultado mostraron un efecto facilitador del RC similar en pacientes y controles; en otras palabras, esta habilidad parece estar preservada en la esquizofrenia. DISCUSION: De forma integrada, los resultados de estos cuatro estudios sugieren la alteracion en la capacidad de activar pensamientos contrafactuales en la esquizofrenia como un deficit cognitivo primario de la enfermedad, relativamente independiente de la gravedad de los sintomas de la enfermedad y que podria considerarse en el futuro como un potencial endofenotipo cognitivo de la enfermedad. Los resultados respecto a la habilidad de generar inferencias contrafactuales son mas heterogeneos y necesitamos mas investigacion que ayude a clarificar estos hallazgos. Finalmente, des de un punto de vista mas optimista, los resultados evidencian una capacidad de activar intenciones conductuales a traves del RC preservada en la esquizofrenia. En general, estos hallazgos refuerzan los resultados previos que sugieren el RC como un candidato potencial para desarrollar programas de rehabilitacion cognitiva disenados para guiar a los pacientes con esquizofrenia en la comprension de una experiencia negativa y en la activacion de las correspondientes intenciones correctivas. Futuras investigaciones deberian estar centradas en tratar de replicar estos resultados con una muestra mas amplia de participantes, asi como para explorar mejor los deficits neurocognitivos subyacentes del pensamiento contrafactual y su asociacion con el funcionamiento psicosocial en esta enfermedad.

5 citations


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

  • ...21 List of Abbreviations BACS Brief Assessment of Cognition in Schizophrenia CAPE-42 Community Assessment of Psychotic Experiences - 42 CATIE Clinical Antipsychotic Trials of Intervention Effectiveness CFT Counterfactual Thinking CGI-S Clinical Global Impression Scale – Severity Section CIT Counterfactual Inference Test dlPFC Dorsolateral Prefrontal Cortex DMN Default Mode Network DSM-III-R Diagnostic and Statistical Manual of Mental Disorders – 3rd ed. revised DSM-IV Diagnostic and Statistical Manual of Mental Disorders – 4th ed....

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  • ...Another further recent functional imaging key finding in schizophrenia is the one evidencing a failure among these patients to deactivate in the medial frontal area which corresponds to one of the two major midline components of the Default Mode Network (DMN)....

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  • ...Investigators of this field have suggested that DMN dysfunction might account for the cognitive impairment associated with schizophrenia due to a failure to divert physiological resources away from the DMN during cognitively demanding tasks (Libby & Ragland, 2011; Pomarol-Clotet et al., 2008a; Whitfield-Gabrieli et al., 2009)....

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  • ...Mental simulation network: engaging regions related to the DMN (Pomarol-Clotet et al., 2008a), this network is activated when mentally deconstructing the present state of affairs –i.e., supporting the core processes for observing and interpreting a situation, mentally altering and re-evaluating....

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  • ...…suggested that DMN dysfunction might account for the cognitive impairment associated with schizophrenia due to a failure to divert physiological resources away from the DMN during cognitively demanding tasks (Libby & Ragland, 2011; Pomarol-Clotet et al., 2008a; Whitfield-Gabrieli et al., 2009)....

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Journal ArticleDOI
TL;DR: The data suggest that hyperconnectivity of distributed brain areas, especially the mPFC, is a neural mechanism for memory function in the absence of one MTL.
Abstract: How the brain supports normal episodic memory function without medial temporal lobe (MTL) structures has not been well characterized, which could provide clues for new therapeutic targets for people with MTL dysfunction-related memory impairment. To characterize brain network supporting effective episodic memory function in the absence of unilateral MTL, we investigated the whole-brain cortical interactions during functional magnetic resonance imaging memory encoding paradigms of words and figures in patients who showed a normal range of memory capacity following unilateral MTL resection and healthy controls (HC). Compared to the HC, the patients showed less activation in the left inferior frontal areas and right thalamus together with greater activation in the many cortical areas including the medial prefrontal cortex (mPFC). Task-based functional connectivity (FC) analysis revealed that the mPFC showed stronger interactions with widespread brain areas in both patient groups, including the hippocampus contralateral to the resection. Moreover, the strength of the mPFC FC predicts the individual memory capacity of the patients. Our data suggest that hyperconnectivity of distributed brain areas, especially the mPFC, is a neural mechanism for memory function in the absence of one MTL.

5 citations


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

  • ...…not only in patients with bipolar disorder and schizophrenia after controlling the memory performance levels of the patients to that of the HC (Pomarol-Clotet et al., 2008; Pomarol-Clotet et al., 2012) but also frequently reported in patients with cognitive impairment such as MCI and AD…...

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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.