Ketamine Reveals Schizophrenia-Like Shift in Brain Network
4 October 2012. Disrupting glutamate signaling blurs the contrast between the brain’s background “default” activity and its task-related engagement, according to a study published online 25 September in Proceedings of the National Academy of Sciences. Led by Phillip Corlett and John Krystal of Yale University in New Haven, Connecticut, the functional magnetic resonance imaging (fMRI) study investigated the effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor blocker that transiently induces features similar to schizophrenia in healthy people. Ketamine induced changes in brain activation that were associated with resulting working memory deficits and negative symptom-like behavior.
The study suggests that the network properties of the brain, which reflect information flow between different regions, can shape cognition and, when disrupted, result in schizophrenia-like thought abnormalities and behavior. Though neuromodulators like dopamine and serotonin are typically associated with network-wide changes, the study argues that glutamate, a fast-acting, workaday neurotransmitter, can achieve something similar.
A picture of the brain’s network of connections has been emerging from the background hum of activity while a person is awake but at rest. This resting state activity highlights a “default-mode network” consisting of a set of interconnected brain regions that powers down once a person begins a task. This task-related deactivation seems critical for cognition (Daselaar et al., 2004), and appears impaired in schizophrenia, with default activity persisting during tasks (see SRF related news story). The new study focused on both the default-mode network and its complement, the task-positive network, which takes over when a person begins to do something. The push-pull between these two networks offers a more comprehensive view of the brain’s connectivity. Because ketamine transiently induces schizophrenia-like symptoms (Krystal et al., 1994)—a finding that originally suggested that underactive glutamate signaling underlies the disorder (see SRF Hypothesis)—it allowed the researchers a chance to investigate a discrete pharmacological perturbation to these networks that might approximate their state in schizophrenia.
First author Alan Anticevic and colleagues scanned the brain activity of 19 healthy participants while they rested and while they performed a working memory task that required them to indicate the location of circles on a screen that had disappeared. Each person was scanned during a saline infusion and during a ketamine infusion. As expected, ketamine impaired working memory, resulting in a significant decrease in correct trials (-8 percent).
Brain activity-wise, the researchers found an “anti-correlated” relationship between the task-positive network and the default-mode network during saline infusion. During rest, the default-mode network predominated, but during the working memory task, it turned off as task-positive network activity emerged. Ketamine, however, attenuated this seesaw action: during the task, default activity dribbled on, and task-positive activity did not reach its usual heights. Consistent with this, measures of functional connectivity between these networks showed decreased connectivity during the task under saline, but not ketamine.
The researchers then turned to computational modeling to understand how ketamine might exert these effects. With a model consisting of a task-activated module and a task-deactivated module, they found that attenuating glutamate signals from excitatory neurons onto inhibitory ones led to disinhibition in the circuit that could recapitulate their fMRI findings. Further simulations suggested that this disinhibition rendered a module hyperactive, and so less able to heed the instructions to turn off from its complementary network. This suggests that the state of local circuitry can alter global networks.
To see whether the ketamine-induced shifts in network activity had consequences for behavior, the researchers related trial-by-trial performance with brain activity. This revealed a significant association with the default-mode network: during saline infusion, correct trials were associated with more suppression of default-mode network regions than incorrect ones, but under ketamine, less suppression occurred during correct trials. This is consistent with the hyperactivity found previously in the default-mode network in schizophrenia (see SRF related news story), and supports the idea that deactivation of this network is critical for working memory and other realms of cognition.
This degree of default-mode network deactivation also correlated with schizophrenia-like symptoms assessed immediately after scanning. Under ketamine, those with the more hyperactive default-mode network during a task also scored higher on negative symptoms severity (r = 0.61, P <0.006). The authors suggest that the default-mode hyperactivity under ketamine may indicate a brain tilted toward a passive, self-reflective state—so much so that it interferes with goal-directed behavior. Other measures of positive and dissociative symptoms did not reach statistical significance.
The study’s pharmacological before-and-after design allows it to sidestep the usual chicken versus egg conundrum that comes with any brain abnormality detected in schizophrenia. Whether ketamine offers a useful approximation of schizophrenia remains to be seen, but the findings support the idea that reduced glutamate signals on interneurons represent a core pathology in schizophrenia (Marín, 2012), and highlight the involvement of the default-mode network.—Michele Solis.
Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ, Niciu MJ, Morgan PT, Surti TS, Bloch MH, Ramani R, Smith MA, Wang XJ, Krystal JH, Corlett PR. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci U S A. 2012 Sep 25. Abstract
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Related News: Default Mode Network Acts Up in SchizophreniaComment by: Vince Calhoun
Submitted 27 January 2009
Posted 27 January 2009
In this work the authors test for differences in the default mode network between healthy controls, patients with schizophrenia, and first degree relatives of the patients. They look at both the degree to which the default mode is modulated by a working memory task and also examine the strength of the functional connectivity. The controls are found to show the most default mode signal decrease during a task, with relatives and patients showing much less. The controls, relatives, and patients show increasing amounts of functional connectivity within the default mode regions. In addition, signal in some of the regions correlated with positive symptoms. The findings in the chronic patients and controls are consistent with our previous work in Garrity et al., 2007, which also showed significantly more functional connectivity in the default mode of schizophrenia patients and significant correlations in certain regions of the default mode with positive symptoms, and in both cases the regions we identified are similar to those shown in the Whitfield-Gabrieli paper. Our work in Kim et al., 2009, was a large multisite study showing significantly fewer default mode signal decreases for the auditory oddball task in chronic schizophrenia patients, again consistent with the Whitfield-Gabrieli paper, but in a different task.
The most interesting contribution of the Whitfield-Gabrieli paper is their inclusion of a first-degree relative group. They found that the first-degree relatives are “in between” the healthy controls and the chronic patients in terms of both the degree to which they modulate the default mode, as well as in their degree of functional connectivity. This has interesting implications in terms of the genetic aspects of the illness and suggests that the default mode may be a potential schizophrenia endophenotype. It will be interesting in future studies to examine both the heritability of the default mode patterns and their genetic underpinnings.
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Related News: Default Mode Network Acts Up in Schizophrenia
Comment by: Edith Pomarol-Clotet
Submitted 28 January 2009
Posted 28 January 2009
The Default Mode Network and Schizophrenia
For a long time functional imaging research has focused on brain activations. However, since 2001 it has been appreciated that there is also a network of brain regions—which includes particularly two midline regions, the medial prefrontal cortex and the posterior cingulate cortex/precuneous—which deactivates during performance of a wide range of cognitive tasks. Why some brain regions should be active at rest but deactivate when tasks have to be performed is unclear, but there is intense speculation that this network is involved in functions such as self-reflection, self-monitoring, and the maintenance of one’s sense of self.
Could the default mode network be implicated in neuropsychiatric disease states? There is evidence that this is the case in autism, and a handful of studies have been also carried out in schizophrenia. Now, Whitfield-Gabrieli and colleagues report that 13 schizophrenic patients in the early phase of illness showed a failure to deactivate the anterior medial prefrontal node of the default mode network when they performed a working memory task. They also find that failure to deactivate is seen to a lesser but still significant extent in unaffected first-degree relatives of the schizophrenic patients, and that the degree of failure to deactivate is associated with both the severity of positive and negative symptoms in the patients.
Importantly, the findings of Whitfield-Gabrieli and colleagues are closely similar to those of another recent study by our group (Pomarol-Clotet et al., 2008), which found failure to deactivate in the medial prefrontal cortex node of the default mode network in 32 chronic schizophrenic patients. This is a striking convergence in the field of functional imaging studies of schizophrenia, which has previously been marked by diverse and often conflicting findings. Additionally, in both studies the magnitude of the difference between patients and controls was large and visually striking. These findings suggest that we may be dealing with an important abnormality which could be close to the disease process in schizophrenia.
If so, what does dysfunction in the default mode network mean? On the one hand, failure to deactivate part of a network whose activity normally decreases when attention has to be turned to performance of external tasks might be expected to interfere with normal cognitive operations. Consistent with this, cognitive impairment is nowadays accepted as being an important, or even a “core” feature of schizophrenia. Perhaps more importantly, could it be that default mode network dysfunction can help us understand the symptoms of schizophrenia? As Whitfield-Gabrieli and colleagues note, if the default mode network is involved in self-reflection, self-monitoring, and maintenance of one’s sense of self, then failure of deactivation might lead to an exaggerated focus on one’s own thoughts and feelings, excessive self-reference, and/or a breakdown in the boundary between the inner self and the external world. The default mode network may thus have the potential to account for two major realms of clinical abnormality in schizophrenia—its symptoms and the cognitive impairment that is frequently associated with them.
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Related News: Default Mode Network Acts Up in Schizophrenia
Comment by: Samantha Broyd, Edmund Sonuga-Barke
Submitted 4 February 2009
Posted 4 February 2009
The surge in scientific interest in patterns of connectivity and activation of resting-state brain function and the default-mode network has recently extended to default-mode brain dysfunction in mental disorders (for a review, please see Broyd et al., 2008). Whitfield-Gabrieli et al. examine resting-state and (working-memory) task-related brain activity in 13 patients with early-phase schizophrenia, 13 unaffected first-degree relatives, and 13 healthy control participants. These authors report hyperconnectivity in the default-mode network in patients and relatives during rest, and note that this enhanced connectivity was correlated with psychopathology. Further, patients and relatives exhibited reduced task-related suppression (hyperactivation) of the medial prefrontal region of the default-mode network relative to the control group, even after controlling for task performance.
The findings from the Whitfield-Gabrieli paper are in accordance with those from a number of other research groups investigating possible default-mode network dysfunction in schizophrenia. For example, in a similar working memory task Pomarol-Clotet and colleagues (2008) have also shown reduced task-related suppression of medial frontal nodes of the default-mode network in 32 patients with chronic schizophrenia. However, the findings are at odds with research reporting widespread reductions in functional connectivity in the resting brain of this clinical group (e.g., Bluhm et al., 2007; Liang et al., 2006). As noted by Whitfield-Gabrieli et al., increased connectivity and reduced task-related suppression of default-mode activity may redirect attentional focus from task-related events to introspective and self-referential thought processes. The reduced anti-correlation between the task-positive and default-mode network in patients further supports and helps biologically ground suggestions of the possibility of an overzealous focus on internal thought. Perhaps even more interestingly, the study by Whitfield-Gabrieli and colleagues suggests that aberrant patterns of activation and connectivity in the default-mode network, and in particular the medial frontal region of this network, may be associated with genetic risk for schizophrenia. Although there are some inconsistencies in the literature regarding the role of the default-mode network in schizophrenia, the work of Whitfield-Gabrieli and others suggests that this network may well contribute to the pathophysiology of this disorder and is relevant to contemporary models of schizophrenia. Indeed, the recent flurry in empirical research investigating the clinical relevance of this network to mental disorder has highlighted a number of possible putative mechanisms that might link the default-mode network to disorder. Firstly, effective transitioning from the resting-state to task-related activity appears to be particularly vulnerable to dysfunction in mental disorders and may be characterized by deficits in attentional control. Sonuga-Barke and Castellanos (2007) have suggested that interference arising from a reduction in the task-related deactivation of the default-mode network may underlie the disruption of attentional control. The default-mode interference hypothesis proposes that spontaneous low-frequency activity in the default-mode network, normally attenuated during goal-directed tasks, can intrude on task-specific activity and create cyclical lapses in attention resulting in increased variability and a decline in task performance (Sonuga-Barke and Castellanos, 2007). Sonuga-Barke and Castellanos (2007) suggest that the efficacious transition from rest to task and the maintenance of task-specific activity may be moderated by trait factors such as disorder. Secondly, the degree of functional connectivity in the default-mode network may highlight problems of reduced connectivity, or excess functional connectivity (e.g., schizophrenia), which suggests a zealous focus on self-referential processing and introspective thought. Thirdly, the strength of the anti-correlation between the default-mode and task-positive networks may also indicate a clinical susceptibility to introspective or extrospective orienting. Finally, future research should continue to examine the etiology of the default-mode network in schizophrenia.
Bluhm, R.L., Miller, J., Lanius, R.A., Osuch, E.A., Boksman, K., Neufeld, R.W.J., Théberge, J., Schaefer, B., & Williamson, P. (2007). Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: Anomalies in the default network. Schizophrenia Bulletin, 33, 1004-1012. Abstract
Broyd, S.J., Demanuele, D., Debener, S., Helps, S.K., James, C.J., & Sonuga-Barke, E.J.S. (in press). Default-mode brain dysfunction in mental disorders: a systematic review. Neurosci Biobehav Rev. 2008 Sep 9. Abstract
Liang, M., Zhou, Y., Jiang, T., Liu, Z., Tian, L., Liu, H., and Hao, Y. (2006). Widespread functional disconnectivity in schizophrenia with resting-state functional magnetic resonance imaging. NeuroReport, 17, 209-213. Abstract
Pomarol-Clotet, E., Salvador, R., Sarro, S., Gomar, J., Vila, F., Martinez, A., Guerrero, A.,Ortiz-Gil, J., Sans-Sansa, B., Capdevila, A., Cebemanos, J.M., McKenna, P.J., 2008. Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default-mode network? Psychological Medicine, 38, 1185–1193. Abstract
Sonuga-Barke, E.J.S., Castellanos, F.X., 2007. Spontaneous attentional fluctuations in impaired states and pathological conditions: a neurobiological hypothesis. Neuroscience Biobehavioural Reviews, 31, 977–986. Abstract
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Related News: Default Mode Network Acts Up in Schizophrenia
Comment by: Yuan Zhou, Tianzi Jiang, Zhening Liu
Submitted 18 February 2009
Posted 22 February 2009
I recommend the Primary Papers
The consistent findings on default-mode network in human brain have attracted the researcher’s attention to the task-independent activity. The component regions of the default-mode network, especially medial prefrontal cortex and posterior cingulate cortex/precuneus, are related to self-reflective activities and attention. Both of these functions are observed to be impaired in schizophrenia. And thus the default-mode network has also attracted more and more attention in the schizophrenia research community. The study of Whitfield-Gabrieli et al. shows a further step along this research streamline.
The authors found hyperactivity (reduced task suppression) and hyperconnectivity of the default network in schizophrenia, and found that hyperactivity and hyperconnectivity of the default network are associated with poor work memory performance and greater psychopathology in schizophrenia. And they found less anticorrelation between the medial prefrontal cortex and the right dorsolateral prefrontal cortex, a region showing increased task-related activity in schizophrenia, whether during rest or task. Furthermore, the hyperactivity in medial prefrontal cortex is negatively related to the hyperconnectivity of the default network in schizophrenia.
There are two main contributions in this work. First, they found significant correlation between the abnormalities in the default mode network and impaired cognitive performance and psychopathology in schizophrenia. Thus they propose a new explanation for the impaired working memory and attention in schizophrenia, and propose a possibility that schizophrenic symptoms, such as delusions and hallucinations, may be due to the blurred boundary between internal thoughts and external perceptions. Secondly, they recruited the first-degree relatives of these patients in this study, and found that these healthy relatives showed abnormalities in the default network similar to that of patients but to a lesser extent. This is the first study investigating the default mode network of relatives of individuals with schizophrenia. This finding indicates that the dysfunction in the default mode network is associated with genetic risk for schizophrenia.
The findings in schizophrenia are consistent with our previous work (Zhou et al., 2007), in which we also found hyperconnectivity of the default mode network during rest. Considering the differences in ethnicity of participants (Chinese in our study) and methodology, the consistency in the hyperconnectivity of the default mode network in schizophrenia is exciting, which supports the possibility that abnormality in the default-mode network may be a potential imaging biomarker to assist diagnosis of schizophrenia. However, this needs to be validated in future studies with a large sample size, due to other contradictory findings, for example, the reduced resting-state functional connectivities associated with the posterior cingulate cortex in chronic, medicated schizophrenic patients (Bluhm et al., 2007). In addition, further studies should focus on default-mode function in different clinical subtypes, as schizophrenia is a complicated disorder. Finally, it should be noticed that the hyperconnectivity of the default-mode network is not exclusively contradictory with hyperconnectivity in other regions, as we previously found (Liang et al., 2006). It is possible that hyperconnectivity and hyperconnectivity coexist in the brains of individuals with schizophrenia and together lead to the complicated symptoms and cognitive deficits.
Bluhm, R. L., Miller, J., Lanius, R. A., Osuch, E. A., Boksman, K., Neufeld, R. W., et al., 2007. Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. Schizophr Bull 33, 1004-1012. Abstract
Liang, M., Zhou, Y., Jiang, T., Liu, Z., Tian, L., Liu, H., et al., 2006. Widespread functional disconnectivity in schizophrenia with resting-state functional magnetic resonance imaging. Neuroreport 17, 209-213. Abstract
Whitfield-Gabrieli, S., Thermenos, H. W., Milanovic, S., Tsuang, M. T., Faraone, S. V., McCarley, R. W., et al., 2009. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci U S A 106, 1279-1284. Abstract
Zhou, Y., Liang, M., Tian, L., Wang, K., Hao, Y., Liu, H., et al., 2007. Functional disintegration in paranoid schizophrenia using resting-state fMRI. Schizophr Res 97, 194-205. Abstract
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Related News: Monkey Model of Schizophrenia Debuts
Comment by: Dan Javitt, SRF Advisor
Submitted 30 September 2013
Posted 30 September 2013
This is an important paper that confirms the role of NMDA receptors in the generation of mismatch negativity (MMN) and, by extension, the potential role of NMDA receptors in the pathophysiology of schizophrenia. As in prior studies with MMN in monkeys, the latency of MMN in monkeys appears to obey the 2/3 rule, which allows cross-species scaling of sensory ERP.
Since our initial report of PCP effects on MMN in monkeys in the late 1990s (Javitt et al., 1996) and subsequent reports on ketamine effects on MMN in humans shortly thereafter (Umbricht et al., 2000), the findings have been extensively replicated in humans. This, however, is the first replication in monkeys and the first to use primarily surface electrodes, and so opens the door to more widespread investigation. In particular, studies in humans are limited to acute administration. However, acute administration of NMDA receptor antagonists only captures a portion of the syndrome. In monkeys, chronic administration of NMDA receptor antagonists is possible and is associated with progressive development of negative-like symptoms (Linn et al., 2007).
As in our earlier report, ketamine treatment reduced MMN-related activity but did not affect responses to rapidly presented, repetitive, standard stimuli, reproducing the pattern of deficit observed in schizophrenia. In this initial study, no other classes of compounds were tested. However, establishment of this model permits testing of a wide range of compounds, including pharmacological probes for other classes of glutamate receptors, or from other transmitter systems (e.g., dopaminergic, cholinergic, GABAergic) that have also been implicated in schizophrenia. Especially during subchronic treatment, the ability to reverse MMN deficits may be an important screening model for potentially psychotherapeutic compounds in schizophrenia and other NMDA receptor-related disorders.
Another important issue that can be addressed using monkey models is the nature and identity of the "frontal generator." It is clear from both MEG and intracranial recording studies that primary generators for MMN are in auditory regions of the superior temporal cortex. Additional, frontal generators are also sometimes reported based upon source analysis. However, unless constrained through physiological means, source localizations can easily produce spurious results. This study uses LORETTA, a common source-localization approach, and identifies sources in frontal and anterior cingulate cortices (ACC), as well as in auditory cortex.
Generators in ACC are unlikely in humans, because they should be detectable by MEG. Nevertheless, an obvious follow-up of this study is to implant intracranial electrodes in those regions detected using LORETTA. If local generators are found, it will give renewed understanding about the relationship between auditory and frontal interaction during MMN generation. If local generators are not found, it will permit refinement of the LORETTA approach and reduction in "false positive" localizations that may, of themselves, complicate understanding of disorders such as schizophrenia.
Finally, a goal of biomarker research is the development of measures that can be implemented in relatively simple species, such as rodents. For complex disorders such as schizophrenia, however, it could be that more complex, primate models are required. As opposed to most primate paradigms, MMN can be obtained even in untrained animals, permitting a development path from rodents through primates and into humans.
Javitt DC, Steinschneider M, Schroeder CE, Arezzo JC. Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia. Proc Natl Acad Sci U S A. 1996;93(21):11962-7. Abstract
Umbricht D, Schmid L, Koller R, Vollenweider FX, Hell D, Javitt DC. Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry. 2000;57(12):1139-47. Abstract
Linn GS, O'Keeffe RT, Lifshitz K, Schroeder C, Javitt DC. Behavioral effects of orally administered glycine in socially housed monkeys chronically treated with phencyclidine. Psychopharmacology (Berl). 2007;192(1):27-38. Abstract
Javitt DC, Spencer KM, Thaker GK, Winterer G, Hajos M. Neurophysiological biomarkers for drug development in schizophrenia. Nature reviews. 2008;7(1):68-83. Abstract
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Related News: Ketamine Elicits Brain State Resembling Early Stages of Schizophrenia
Comment by: Hugo Geerts
Submitted 26 August 2014
Posted 26 August 2014
This is a very interesting contribution to improve the understanding of the
progressive nature of schizophrenia pathology. Ketamine-induced effects
have been used for a long time in healthy volunteers or in animal models,
both rodents and non-human primates to "mimic" schizophrenia pathology. The
observation that ketamine mimics more the very early schizophrenia or the
at-risk state but not the more chronic pathology helps to explain the
dissociation between effects of compounds in ketamine-induced deficits and
in chronic schizophrenia, for example, nicotine (D'Souza et al., 2012), glycine
transport inhibitor (D'Souza et al., 2012), haloperidol (Oranje et al., 2009), and lamotrigine (Goff et al., 2007).
The impact of these findings, if reproduced in a longitudinal study, is very
important. This model of ketamine-induced deficit can be used in animals to
test new experimental interventions in very early psychosis or in at-risk
subjects. This is a patient group that is currently underserved in terms of
therapeutic interventions and for which there is great interest. For the
first time, we now have a model that mimics important aspects of the early
schizophrenia pathology, and the hope is that when addressing these changes
with the right medication early on, one could postpone or delay the onset of
overt schizophrenia pathology, which could be the beginning of a preventive
D'Souza DC, Ahn K, Bhakta S, Elander J, Singh N, Nadim H, Jatlow P, Suckow RF, Pittman B, Ranganathan M. Nicotine fails to attenuate ketamine-induced cognitive deficits and negative and positive symptoms in humans: implications for schizophrenia. Biol Psychiatry . 2012 Nov 1 ; 72(9):785-94. Abstract
D'Souza DC, Singh N, Elander J, Carbuto M, Pittman B, Udo De Haes J, Sjogren M, Peeters P, Ranganathan M, Schipper J. Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence. Neuropsychopharmacology . 2012 Mar ; 37(4):1036-46. Abstract
Oranje B, Gispen-de Wied CC, Westenberg HG, Kemner C, Verbaten MN, Kahn RS. Haloperidol counteracts the ketamine-induced disruption of processing negativity, but not that of the P300 amplitude. Int J Neuropsychopharmacol . 2009 Jul ; 12(6):823-32. Abstract
Goff DC, Keefe R, Citrome L, Davy K, Krystal JH, Large C, Thompson TR, Volavka J, Webster EL. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol . 2007 Dec ; 27(6):582-9. Abstract
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