Schizophrenia Research Forum - A Catalyst for Creative Thinking

Default Mode Network Acts Up in Schizophrenia

27 January 2009. People with schizophrenia show changes in the activity of an interconnected network of brain regions that is involved in memory and self-reflection, according to a study out in this week’s PNAS online edition. The work, from Susan Whitfield-Gabrieli and colleagues at MIT, used functional magnetic resonance imaging (fMRI) to look at the default mode network, a distributed network that is active when the brain is resting and that powers down during focused mental tasks. The results indicate that the network is hyperactive and hyperconnected in people with schizophrenia, and could be contributing to their symptoms. The network is also affected in healthy, first-degree relatives of subjects, suggesting that the changes could be part of the genetic risk for the disease.

The results fit with the idea that there are widespread deficiencies in cortical processing in schizophrenia, and suggest that these deficiencies affect a brain network thought to be responsible for self-awareness and internal reference.

In other network news, three papers in the January 19 edition of Nature online show progress toward the elusive goal of mapping neuronal networks in the cortex at the finer level of single cells and their synaptic partners. The results offer techniques that will be useful to probe the alterations in micro-scale cortical organization that underlie the functional changes seen in schizophrenia.

Cognitive connections
The concept of the default mode network, a distributed neural network that is active when the brain is resting and that powers down during focused mental tasks, was only first published in 2001, but it has become a hot topic in cognitive neuroscience. The network, which includes the medial prefrontal cortex, the posterior cingular cortex/precuneous, and the lateral parietal cortex, activates during daydreaming, self-referential thought, and during some kinds of memory retrieval. The seesaw deactivation of the default network and activation of task-related brain regions, which may reflect the dynamic allocation of cognitive resources between internal and external demands, is critical for peak performance on memory tasks.

Previous studies have shown changes in the default mode function in people with schizophrenia (Garrity et al., 2007; Zhou et al., 2007; Pomarol-Clotet et al., 2008). The new work adds to those studies by looking at activity in relatives and by correlating changes in the network with schizophrenia pathology.

In the study, Whitfield-Gabrieli and coworkers performed fMRI scans of subjects while they were idle, and then when they engaged in a simple working memory test. The data allowed them to assess both resting network activity, and the extent of deactivation that occurred during a task that required concentration. The study compared 13 volunteers with early-phase schizophrenia, 13 unaffected first-degree relatives, and 13 healthy controls. When subjects performed the recall test, activation occurred in the dorsolateral prefrontal cortex. As expected, the activation was higher in patients and relatives compared to controls. At the same time, deactivation of the default mode network was decreased in patients and relatives compared to controls. Overall, the deactivation in the default network and activation of task-related areas strongly correlated in control subjects, but the seesaw effect was much weaker in patients and relatives. The result was a consistent hyperactivity of the default network, which correlated with worse performance in the memory task.

Altered brain connectivity of default brain network in persons with schizophrenia and first-degree relatives. Colored areas represent an interconnected network of brain regions that show synchronized activity (overlapping black and blue traces) when subjects rest and allow their minds to wander. The amount of synchrony, which reflects the strength of functional connections between the different areas, is increased in patients with schizophrenia. First-degree relatives of persons with the illness also show some increase, although less than patients. Black circle: medial prefrontal cortex. Blue circle: posterior cingulate/precuneous. Image credit: Susan Whitfield-Gabrieli, McGovern Institute for Brain Research at MIT

Measurement of the default network connectivity, or the extent to which regions activate together, showed a stronger connectively between the medial prefrontal cortex and the precuneous and the rest of the default network in patients and relatives. This was seen whether connectivity was measured at rest or during the task. Like the deactivation defect, higher connectively also correlated with worse working memory performance.

The strength of connectivity and defect in deactivation correlated with stronger schizophrenia symptoms, suggesting that the default mode network could play an important role the cognitive and clinical symptoms of schizophrenia. Defects in deactivation could explain problems with working memory and attention. In addition, the authors point out that the default mode network is normally activated during internal, self-referential thought. “Hyperactivity of the default network may blur the normal boundary between internal thoughts and external perceptions,” this write. “Indeed, many symptoms of schizophrenia involve an exaggerated sense of self-relevance in the world, such as paranoid ideation that individuals and groups are conspiring against the patient, and a blurring of internal reflection and external perception, such as hallucinations.”

The finding that unaffected relatives show changes in the default network suggests that the activity stems from genetic risk and is causal, rather than just a consequence of the disease, Whitfield-Gabrieli told SRF. “In the future, it may be possible to use these fMRI measures as a way of diagnosing disease, or to figure out how patients are responding to treatment,” she said.

Other diseases where default mode network activity is known to be altered include autism, epilepsy, depression, attention deficit/hyperactivity disorder, and Alzheimer disease (for a comprehensive review of the literature of default mode activity and disease, see Broyd et al., 2008).

Connect the neurons
Networks like the default mode involve widely distributed areas of the brain, but no matter how far-flung their components may be, the basic unit of any network comes down to neuron-to-neuron communication at individual synapses. A detailed understanding of brain circuits, and how they are altered in schizophrenia, will require a map of the wiring between individual neurons. However, it has been nearly impossible to tease out exact contacts in the spaghetti-like tangle of axons, dendrites, and cell bodies that make up brain tissue. In the January 18 online edition of Nature, three different groups report their efforts to unravel this knotty problem by combining single cell recording with sophisticated imaging and other techniques.

First, Solange Brown and Shaul Hestrin of Stanford University looked at the local connections among three classes of cortical neurons that project over long distances to the contralateral cortex, the contralateral striatum, or the superior colliculus. After retrograde labeling of projections in live mice to distinguish the different kinds of neurons, the researchers simultaneously recorded activity in sets of four cells in cortical slices. By stimulating each cell in turn and watching the others’ responses, Brown and Hestrin showed they could identify local cortical connections with high success. The tendency of cells to make local connections was not random, or simply based on proximity, but depended on the identities of both the presynaptic and postsynaptic cells. For example, a neuron that projected to the contralateral cortex (a corticocortical neuron) was four times more likely to make a synapse with a local corticotectal neuron than with another corticocortical neuron. The results suggest a way to unravel the local circuit architecture in the cortex.

In a second paper, researchers from Matthew Larkum’s lab at the University of Bern in Switzerland used fiber optic imaging to measure dendritic calcium changes and uncover a cortical inhibitory microcircuit in living rats. In the circuit, they found, inhibitory interneurons govern the graded calcium response in L5 pyramidal neuron dendrites after sensory stimuli. The results help explain how neurons can respond to sensory input over a large dynamic range by utilizing cortical micronetworks.

Finally, Karel Svoboda and colleagues of the Howard Hughes Medical Institute in Ashburn, Virginia, traced out an excitatory circuit using photoactivation of neurons expressing channelrhodopsin (Wang et al., 2007) to map out points of contact. Taking cortical slices with channelrhodopsin expressed in axons, first author Leopoldo Petreanu and colleagues used a laser beam to stimulate local neurotransmitter release while simultaneously recording from barrel cortex pyramidal neurons. If the axons made a synapse on the recorded cell, a postsynaptic excitatory current would be triggered. By directing channelrhodopsin expression to different layers of the cortex whose axons overlap with the pyramidal cell dendrites of the barrel cortex, the investigators were able to map input from the thalamus, cortical layers 4, 2/3, 4, L2/3, and part of the motor cortex to the dendrites of L3 and L5 pyramidal neurons. They found many of the known connections, as well as some new ones. In addition, the mapping revealed a high degree of spatial specificity, with different inputs mapping onto more distal or apical locations on the dendrites. By allowing the high-resolution look at neuronal circuits, the technique should help achieve a micro-scale, comprehensive picture of the hardware of the brain.—Pat McCaffrey.

Whitfield-Gabrieli S, Thermenos HW, Milanovic S, Tsuang MT, Faraone SV, McCarley RW, Shenton ME, Green AI, Nieto-Castanon A, LaViolette P, Wojcik J, Gabrieli JDE, Seidman LJ. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. PNAS Early Edition. 2009 Jan 19. Abstract

Murayama M, Pérez-Garci E, Nevian T, Bock T, Senn W, Larkum ME. Dendritic encoding of sensory stimuli controlled by deep cortical interneurons. Nature. 2009 Jan 18. Abstract

Brown SP, Hestrin S. Intracortical circuits of pyramidal neurons reflect their long-range axonal targets. Nature. 2009 Jan 18. Abstract

Petreanu L, Mao T, Sternson SM, Svoboda K. The subcellular organization of neocortical excitatory connections. Nature. 2009 Jan 18. Abstract

Comments on News and Primary Papers
Comment 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.

View all comments by Vince CalhounComment 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.

View all comments by Edith Pomarol-ClotetComment by:  Samantha BroydEdmund 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

View all comments by Samantha Broyd
View all comments by Edmund Sonuga-BarkeComment by:  Yuan ZhouTianzi JiangZhening 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

View all comments by Yuan Zhou
View all comments by Tianzi Jiang
View all comments by Zhening Liu

Comments on Related News

Related News: Schizophrenia-associated Variant in ZNF804A Gene Affects Brain Connectivity

Comment by:  James WaltersMichael Owen (SRF Advisor)
Submitted 3 June 2009
Posted 3 June 2009

Andreas Meyer-Lindenberg’s group examine the association between a single nucleotide polymorphism (SNP), rs1344706 in gene ZNF804A, recently identified as a risk factor for schizophrenia in a genome-wide association study (GWAS) (O'Donovan et al., 2008) and functional connectivity as measured by fMRI. The attraction of this polymorphism for a study of this kind is twofold. First, statistically speaking it is the most robust SNP association with schizophrenia reported to date. Second, because a single variant shows strong evidence for association, which is not the case for other reported associations, it is possible to specify a priori for the gene in question directional hypotheses in relation to potential neurocognitive correlates. This militates against the generation of false positives through the testing of multiple SNPs and haplotypes which has rendered problematic the interpretation of at least some previous genetic imaging studies (Walters and Owen, 2007). The function of ZNF804A is unknown but the fact that it contains a zinc finger domain suggests that it may be a transcription factor. It is hoped that the characterization of the actions of SNPs identified by GWAS will identify new pathogenic mechanisms of psychosis. One way in which this can be achieved is via approaches such as that taken in this article.

Esslinger et al. report variations in functional connectivity in 115 healthy individuals according to rs1344706 risk variant status. Given the association of ZNF804A with both schizophrenia and bipolar disorder they employed two fMRI tasks thought to be sensitive to altered function in these disorders: the N Back (2back) task is sensitive to deficits of dorsolateral prefrontal cortex (DLPFC) function in schizophrenia and an emotional face-matching task is linked with amygdala function and thought to be relevant to mood disorder. They compared the activity in these regions and functional connectivity (using time-series correlation) between the three rs1344706 genotype groups.

No differences between genotype groups were found for activation, but the authors did identify altered connectivity with the most activated DLPFC locale. Risk-allele carriers were shown to exhibit a lack of uncoupling of activity (increased functional connectivity) between the right DLPFC and left hippocampus during the 2-back task as well as decreased connectivity within right DLPFC and between right and left DLPFC. Risk variant carriers also showed wide ranging increased connectivity between right amygdala and other anatomical regions. The majority of these findings showed a risk allele dose effect.

The increased DLPFC/hippocampus functional connectivity in carriers of the risk allele is potentially the most interesting finding given that Meyer-Lindenberg’s group has previously shown that those with schizophrenia show increased functional connectivity between DLPFC and hippocampus during working memory (Meyer-Lindenberg et al., 2005). Notes of caution in this regard are that 1) the biological, anatomical or functional significance of fMRI determined functional connectivity is yet to be established and 2) other functional connectivity studies in schizophrenia have produced conflicting results Lawrie et al., 2002. Nonetheless, it is interesting that rs1344706 may affect co-ordination of activity between these two brain regions given their seeming importance in psychotic conditions. The significance of these findings to cognitive deficits and other symptom domains needs further investigation particularly as others have postulated dysconnectivity has more relevance to first rank psychotic symptoms (Stephan et al., 2009).

It is likely that genome-wide association approaches will continue to identify genes with unknown neural function and so approaches such as this are likely to be a valuable way of identifying the biological/neural pathways that involve these genes. It is also imperative that as in this study methodology is employed to allow for multiple testing and also that negative findings are reported. We would also suggest caution until these findings are replicated. As well as such approaches in humans, it is also important to investigate the effects of identified variants at other levels of analysis from gene expression to behavioural genetics work. Finally we find it reassuring that GWAS approaches seem to be successful in identifying risk variants whose functions can be investigated using methods such as that taken by Esslinger et al.


O'Donovan MC, Craddock N, Norton N, et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genetics. 2008;40(9):1053-1055. Abstract

Walters JT, Owen MJ. Endophenotypes in psychiatric genetics. Mol Psychiatry. 2007;12(10):886-890. Abstract

Meyer-Lindenberg AS, Olsen RK, Kohn PD, et al. Regionally Specific Disturbance of Dorsolateral Prefrontal-Hippocampal Functional Connectivity in Schizophrenia. Archives of General Psychiatry. 2005;62(4):379-386. Abstract

Lawrie SM, Buechel C, Whalley HC, Frith CD, Friston KJ, Johnstone EC. Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biological Psychiatry. 2002;51(12):1008-1011. Abstract

Stephan KE, Friston KJ, Frith CD. Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring. Schizophr Bull. 2009;35(3):509-527. Abstract

View all comments by James Walters
View all comments by Michael Owen

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 strategy.


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

View all comments by Hugo Geerts

Related News: Ketamine Elicits Brain State Resembling Early Stages of Schizophrenia

Comment by:  Alexandre Seillier
Submitted 9 September 2014
Posted 11 September 2014

The "Ketamine Model" Revived?
Despite the seminal review by Jentsch and Roth arguing that long-term, rather than acute administration of NMDA antagonists, such as phencyclidine (PCP) and ketamine, may more isomorphically model schizophrenia (Jentsch and Roth, 1999), acute ketamine remained one of the most widely utilized pharmacological models in both humans and rodents. Recently, Dawson and co-workers added to the accumulating body of evidence that "alterations in brain circuitry that result from chronic, but not from acute, NMDA receptor blockade most accurately reflect the systems level differences in brain network functioning seen in schizophrenia" (Dawson et al., 2014a; Dawson et al., 2014b). Indeed, using brain network connectivity, they reported that, "at a systems level, the mechanisms through which acute ketamine treatment induces schizophrenia-like symptoms may be profoundly divergent from those that contribute to these symptoms in the disorder."

This new study by Anticevic et al. (2014) might have resolved the paradox of acute ketamine-induced hyperfrontality given the hypofrontality observed in schizophrenia. As previously shown in both healthy humans and mice (Dawson et al., 2014a; Driesen et al., 2013), acute ketamine administration was associated with increased prefrontal cortex connectivity. On the other hand, whereas chronic schizophrenics had reduced prefrontal cortex functional connectivity, patients in the early stage of schizophrenia showed increased prefrontal cortex functional connectivity. As stated by the authors, "these data point to a qualitative difference between NMDAR antagonist and chronic schizophrenia effects, suggesting that ketamine's effect on prefrontal cortex connectivity may be more relevant to particular illness stages."

Longitudinal studies will be necessary to confirm that the "phase of illness is an important moderator of the prefrontal cortex functional connectivity in schizophrenia." The authors also addressed some discrepancies that need to be highlighted. First, the reduced and the increased prefrontal cortex functional connectivity in chronic versus early-stage schizophrenia, respectively, were observed in distinct prefrontal areas, namely the right middle frontal gyrus and the left superior frontal gyrus, respectively. Second, the cross-validation of the pharmacological and clinical analysis failed to reach significance; i.e., acute ketamine did not significantly change connectivity in the regions identified in the clinical study. Although it has limitations, this study should inform the application of acute ketamine as a translational model that may better approximate some early stage of schizophrenia.


Dawson N, McDonald M, Higham DJ, Morris BJ, Pratt JA (2014a) Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks. Neuropsychopharmacology 39:1786-98. Abstract

Dawson N, Xiao X, McDonald M, Higham DJ, Morris BJ, Pratt JA (2014b) Sustained NMDA receptor hypofunction induces compromised neural systems integration and schizophrenia-like alterations in functional brain networks. Cereb Cortex 24: 452-464. Abstract

Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D'Souza DC et al (2013) Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine. Mol Psychiatry 18:1199-1204. Abstract

Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20: 201-225. Abstract

View all comments by Alexandre Seillier

Related News: Ketamine Elicits Brain State Resembling Early Stages of Schizophrenia

Comment by:  Albert Adell
Submitted 10 September 2014
Posted 16 September 2014

The paper by Anticevic and co-workers, as well as the commentary by Hugo Geerts, points to a very interesting issue on the similitude of the ketamine model with schizophrenia. In a previous mini-review, we anticipated that it would be conceivable that acute administration of NMDA receptor antagonists would lead to a reversible malfunctioning of PV-containing interneurons, whereas in schizophrenia, a damage of these neurons may take place at early stages of neurodevelopment (Adell et al., 2012). In summary, acute NMDA antagonism would resemble the early stage of schizophrenia, whereas chronic exposure better models the more chronic pathology of the illness.


Adell A, Jiminez-Sanchez L, Lopez-Gil X, Roman T. Is the Acute NMDA Receptor Hypofunction a Valid Model of Schizophrenia? Schizophr Bull 38(1): 9-14. Abstract

View all comments by Albert Adell