Schizophrenia Research Forum - A Catalyst for Creative Thinking
Home Profile Membership/Get Newsletter Log In Contact Us
 For Patients & Families
What's New
Recent Updates
SRF Papers
Current Papers
Search All Papers
Search Comments
News
Research News
Conference News
Plain English
Forums
Current Hypotheses
Idea Lab
Online Discussions
Virtual Conferences
Interviews
Resources
What We Know
SchizophreniaGene
Animal Models
Drugs in Trials
Research Tools
Grants
Jobs
Conferences
Journals
Community Calendar
General Information
Community
Member Directory
Researcher Profiles
Institutes and Labs
About the Site
Mission
History
SRF Team
Advisory Board
Support Us
How to Cite
Fan (E)Mail
The Schizophrenia Research Forum web site is sponsored by the Brain and Behavior Research Foundation and was created with funding from the U.S. National Institute of Mental Health.
Research News
back to News Search
Default Mode Network Acts Up in Schizophrenia
View related comments: Alzheimer Research Forum

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.

References:
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...  Read more


View all comments by Vince Calhoun

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...  Read more


View all comments by Edith Pomarol-Clotet

Comment 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...  Read more


View all comments by Samantha Broyd
View all comments by Edmund Sonuga-Barke

Comment 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,...  Read more


View all comments by Yuan Zhou
View all comments by Tianzi Jiang
View all comments by Zhening Liu
Submit a Comment on this News Article
Make a comment on this news article. 

If you already are a member, please login.
Not sure if you are a member? Search our member database.

*First Name  
*Last Name  
Affiliation  
Country or Territory  
*Login Email Address  
*Confirm Email Address  
*Password  
*Confirm Password  
Remember my Login and Password?  
Get SRF newsletter with recent commentary?  
 
Enter the code as it is shown below:
This code helps prevent automated registrations.

I recommend the Primary Papers

Please note: A member needs to be both registered and logged in to submit a comment.

Comment:

(If coauthors exist for this comment, please enter their names and email addresses at the end of the comment.)

References:


SRF News
SRF Comments
Text Size
Reset Text Size
Email this pageEmail this page

Share/Bookmark
Copyright © 2005- 2014 Schizophrenia Research Forum Privacy Policy Disclaimer Disclosure Copyright