Summer of Salience: Insula Fingered in Schizophrenia
September 10, 2013. Modern brain imaging has allowed researchers to start mapping networks of brain areas that carry out different tasks (for review, see Bressler and Menon, 2010). Of particular interest to schizophrenia researchers is the "salience network," which is thought to monitor a person’s immediate needs, select the stimuli most relevant to those needs, and feed them to the "central executive network" for further processing to ultimately guide behavior. These two networks do not appear to talk to each other as they should in schizophrenia, and two recent studies focus the blame for this on a key component of the salience network, the insular cortex.
By tracking the timing of brain activation with functional magnetic resonance imaging (fMRI) in people at rest, the two studies find a breakdown in how the anterior insula shapes activity in the dorsolateral prefrontal cortex (DLPFC)—a key member of the central executive network—in schizophrenia. Though fMRI studies often focus on functional connectivity between brain regions, as measured by simultaneous activity in any two regions, these studies examined “effective connectivity,” which measures how activity in one region precedes or predicts activity in another region.
The first study, led by Lauren Moran of the Maryland Psychiatric Research Center in Baltimore and published online April 25 in Biological Psychiatry, focused on selected brain regions and found that, in schizophrenia, the right anterior insula did not modulate the central executive network as it should. The second study, led by Lena Palaniyappan in collaboration with Peter Liddle at the University of Nottingham in the United Kingdom and published August 21 in Neuron, found much the same thing, but through a more agnostic, brainwide approach. Not only did the anterior insula fail to influence the DLPFC in schizophrenia as it did in controls, but feedback from the DLPFC to the anterior insula was also weaker than normal.
"This story is evolving rapidly and in an exciting direction," said Angus MacDonald, SRF advisor and researcher at the University of Minnesota, who was not involved in the studies. "There is specificity of the relationships as demonstrated by convergence of these studies."
The findings suggest a central role for the insula in schizophrenia. Though structural and functional anomalies in the insula are consistently found in the disorder (e.g., Ellison-Wright et al., 2008), these often take a back seat to findings in frontal or temporal regions. The two new studies suggest that well-known frontal dysfunctions in schizophrenia could stem from weak connections with the anterior insula.
The findings also bolster the idea that schizophrenia’s pathology involves disrupted interactions between large-scale networks within the brain. Disruptions in how networks communicate with each other in schizophrenia first emerged in studies of the default-mode network, a collection of brain regions activated when a person is resting quietly and suppressed when one is doing a task. In schizophrenia, this network is not adequately suppressed during tasks, suggesting a difficulty in disengagement from an introspective state (see SRF related news story).
The new research suggests this may be due to problems with the insula-containing salience network, which normally orchestrates the switch between the default-mode network and the central executive network, which enables task performance (Menon and Uddin, 2010). Consistent with this, another recent study found decreased functional connectivity within the anterior insula in schizophrenia, and this correlated with disturbed interactions between the salience network and the central executive network, as well as with severity of negative symptoms (Manoliu et al., 2013).
“The problem is not simply in one of these networks, but rather in the switching between the two networks,” Palaniyappan told SRF. “This is revealing because we know that people with schizophrenia find it very difficult to switch between their internal representations, and they find it hard to process external information as well.”
Centered on salience
“These studies build on and modify the leading hypothesis of this time, which, in my opinion, is aberrant salience," MacDonald wrote to SRF. The aberrant salience hypothesis of schizophrenia proposes that faulty dopamine signals incorrectly assign importance to innocuous elements of a person’s experience (Kapur, 2003), thus producing the disordered thinking and delusions of psychosis. The new findings may be seen as a brain network-based extension of this, in that a malfunctioning salience network does not flag the most relevant things in a person’s environment.
“The insula takes in signals from every part of the body and creates a kind of neuronal readiness to orient to the most appropriate things,” Palaniyappan said. For example, hunger signals from the gut would create a neuronal readiness in the brain to pay attention to any sign of food that might come along. Problems with this state of readiness, which Palaniyappan calls “proximal salience,” would mean that the things that matter most to people’s well being would not necessarily capture their attention.
Although effective connectivity requires looking at the timing of activations across the brain, the poor temporal resolution of fMRI precludes any firm conclusions about which area directly drives another. Nevertheless, researchers can get a sense of the direction of information flow between them.
In the Biological Psychiatry study, first author Moran and colleagues found a reduced outflow of activity from the right dorsal anterior insula. Based on brain activity measured in 44 people with schizophrenia and 44 healthy controls, the results were the same for two methods of measuring effective connectivity. In controls, activity in the anterior insula was followed by robust activity in regions belonging to the central executive network, including the DLPFC, as well as in regions of the default-mode network, including the posterior cingulate cortex (PCC) and the lateral parietal cortex. In schizophrenia, however, activity in the anterior insula did not switch these networks on. Specifically, the usual follow-up activity in the DLPFC, PCC, and lateral parietal cortex did not emerge.
As in previous studies of inter-network connectivity, these results came from people asked to simply rest in the scanner. This raises questions for some about how to interpret any differences found in brain activity in people with a mental illness, who may experience the scanner differently (Buckner et al., 2013). Moran’s study also measured brain activity while study participants were engaged in a sustained attention task, which might engage the brains of both groups more similarly. Even then, reductions in anterior insula outflow were found in schizophrenia compared to controls, particularly to the default-mode network, and these correlated with task performance.
In the Neuron study, first author Palaniyappan and colleagues imaged brain activity in 38 people with schizophrenia and 35 healthy controls while they rested. To find the region that was maximally influenced by right anterior insula activity, the researchers compared right anterior insula activity in one scan with activity in all brain voxels in the next scan, taken 2.5 seconds later. For both controls and people with schizophrenia, the DLPFC turned up as a region whose activity correlated with earlier anterior insula activity; in the schizophrenia group, however, this correlation was weaker than in controls, indicating that the anterior insula had a weaker than usual influence on the DLPFC. When the researchers looked across the brain for neural repercussions of DLPFC activity, the anterior insula turned up: In both groups, its activity was negatively correlated with earlier DLPFC activity (indicating a decrease in activity following DLPFC activity), but in schizophrenia, this correlation was weaker.
These data suggest that the right anterior insula and the DLPFC do not exert normal levels of control over each other in schizophrenia. This disruption may be a core feature of the disorder, as a measure of the extent of this “loop failure” varied with illness severity but not with antipsychotic dosage.
Palaniyappan noted that the resting-state paradigm he used avoids performance-related differences in brain activity that might occur between the two groups. Still, he said he expected a complementary task-based study would give a more pronounced effect than what was found here.
The researchers also reported a decrease in influence from the visual cortex onto the anterior insula in schizophrenia compared to controls. This suggests a chain reaction: The visual cortex doesn’t send enough signals to the insula, the insula doesn’t send enough signals to the frontal cortex, and the frontal cortex does not provide the usual feedback to the insula. Though all correlational, the results recall bottom-up theories of schizophrenia in which impaired sensory processing brings about its complex symptoms (Javitt, 2009, and see SRF related news story).
The new results put the insula at the center of a model of information processing in schizophrenia that can be further tested with methods such as magnetoencephalography (MEG), which better captures the timing of brain activations, or other task-based schemes. The intertwined nature of the insula and frontal cortex suggests that modulating one, possibly through non-invasive stimulation methods, may rehabilitate the other. The results highlight the interconnected nature of the brain and make steps toward understanding which connections matter to schizophrenia.—Michele Solis.
Moran LV, Tagamets MA, Sampath H, O'Donnell A, Stein EA, Kochunov P, Hong LE. Disruption of anterior insula modulation of large-scale brain networks in schizophrenia. Biol Psychiatry. 2013 Sep 15;74(6):467-74. Abstract
Palaniyappan L, Simmonite M, White TP, Liddle EB, Liddle PF. Neural primacy of the salience processing system in schizophrenia. Neuron. 2013 August; 79: 814-828. 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: Deconstructing Negative Symptoms in Schizophrenia
Comment by: Laurie Kimmel
Submitted 25 October 2012
Posted 26 October 2012
As a clinician, I find this research encouraging.
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