The concept of salience network dysfunction in schizophrenia: from neuroimaging observations to therapeutic opportunities Lena Palaniyappan1, Thomas P.

White2, Peter F. Liddle1

Division of Psychiatry, Institute of Mental Health, University of Nottingham, Department of Psychosis Studies, Institute of Psychiatry, Kings College London,

Nottingham, UK.
2

UK.

Key words: Anterior cingulate, Brain Network Modulation, Dopamine, Glutamate, Insula, Plasticity, Salience network, Schizophrenia. Number of words: Abstract: 181 Article: 7213 Figures: 1 Tables: 1 Supplementary Materials: 1

Address correspondence to: Dr. Lena Palaniyappan, Room 09, C Floor, Institute of Mental Health, University of Nottingham Innovation Park, Triumph Road, Nottingham, NG7 2TU, England, United Kingdom. Phone: +44 (115) 823 0407; Fax: 44 (115) 823 0433; E-mail: Lena.Palaniyappan@nottingham.ac.uk

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Abstract

A large body of neuroimaging literature suggests that distributed regions in the brain form coordinated large scale networks that show reliable patterns of connectivity when observed using either functional or structural magnetic resonance imaging (MRI) methods. Functional activation within these networks provides a robust and reliable representation of dynamic brain states observed during information processing. One such network comprised of anterior fronto-insular cortex (aFI) and anterior cingulate cortex (ACC) is called the Salience Network (SN). SN has been identified as a system that enables the switch between various dynamic brain states. SN dysfunction has been proposed as a mechanistic model for several core symptoms of schizophrenia. In this review, we explore how various risk factors of schizophrenia could operate through the dysfunctional SN to generate symptoms of psychosis. We also consider the putative neurochemical basis for the SN

dysfunction in schizophrenia, and suggest that the SN dysfunction is a viable therapeutic target for a combined pharmacological and cognitive training treatment approach. This combination approach, termed as Brain Network Modulation, could exploit neuronal plasticity to reverse a key pathophysiological deficit in schizophrenia.

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Introduction

Our perceptual fields are filled with various stimuli, most of which are not worthy of effortful cognitive processing. Selection and evaluation of suitable stimuli to update the internal model of the external world is a key feature of successful adaptation and survival for any organism. Stimuli that provide instinctual gratification or threat are often regarded as salient for further processing (incentive salience). A large number of stimuli that are not inherently rewarding or threatening are also processed further provided they are pertinent to a task at hand (behavioural relevance). But whether a stimulus is considered as gratifying, threatening or behaviourally salient depends on the appraisal of the bodily state (interoception). A gentle tap on your shoulder may elicit a startle and fright when you are not expecting any company. The same stimulus may hardly elicit any response if you are dancing in a crowded night-club. This also suggests that stimuli that violate our expectations demand our response (predictive surprise). Interoceptive state also sets the context that influences the response offered to a selected stimulus. At times, all that is required may be a change in the expectancy of a stimulus with no further action. In other instances, a motor act may be required, often accompanied by some strengthening of the association between the stimulus and the response. Thus stimulus evaluation and response demands swift changes in the patterns of distributed brain activity (or brain states) between a self-directed or resting mode and a task-processing or executive mode, depending on the interoceptive context.

The term proximal salience is applied to a momentary state of neuronal readiness generated by any stimulus that is conspicuous due to incentive valence, behavioural relevance or expectancy violation and leads to a change in the brain state (1). Accumulating evidence from neuroimaging studies in healthy individuals indicates that the seat of this proximal salience function is localized in the Salience Network (SN)(2, 3). SN is comprised of the cortical regions - anterior fronto-insular cortex (aFI) and anterior cingulate (ACC), the subcortical regions - putamen and thalamus(2, 3), and lobule VI of neocerebellum(4). Though the presence of monosynaptic connections between these nodes are yet to be established in humans, indirect evidence for their existence has been inferred using various neuroimaging modalities, especially the observed co-activation patterns in the fmRI and the use of DTI (58). Evidence from studies of effective connectivity indicate that the aFI plays a causal role in switching between task positive and task-negative/resting brain states (911).
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Multitudinous functional neuroimaging studies involving painful stimuli, disgusting stimuli, those with unpredictable relationships with outcome, and those signalling errors further implicate aFI and ACC regions as a cortical salience response system(1214). It is important to note that in addition to the cortical component of the SN, populations of neurons within the striatum have been seen to exhibit a signal which mimics the prediction error signal when processing several salience-related features such as reward values (15, 16) novelty, aversion and intensity(17, 18). This suggests that a subcortical component is crucial for the role of the SN in information processing(2). aFI also has rich connections with unimodal sensory areas and multimodal cortical regions that constitute various distributed networks such as the default mode network (DMN) (6, 19, 20). Recently, dynamic causal modeling has been employed to demonstrate that direct thalamo- insular connections can bypass primary sensory cortices to allow fast transmission of information from subcortical structures to multimodal cortical areas, allowing early detection of salient events and, facilitating immediate response if appropriate(21).

The construct of SN and proximal salience is highly relevant for schizophrenia, where reality distortion symptoms suggestive of disturbances in the motivational salience and predictive coding(22), and cognitive symptoms suggestive of deficits in processing task relevant information(23) are seen. Several clinical stages (the prodrome, early stage/first episode and chronic stage) are notable in the natural course of schizophrenia(24). Though a definite diagnosis of schizophrenia using current clinical criteria is difficult during the prodrome, neuroimaging(25, 26) investigations in high-risk individuals who exhibit prodromal symptoms suggest continuity in the pathophysiology across the clinical stages. Crucial cognitive deficits that are linked to later functional disability such as impairments in executive function, working memory and verbal fluency are apparent during the at-risk stage(27).

In the following sections, we will consider the neuroimaging evidence for the SN dysfunction in schizophrenia; review the putative neurochemical basis and bring together observations suggesting that the deficits in proximal salience in schizophrenia might be addressed therapeutically using a combination of pharmacological and cognitive training strategies.

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2. Evidence for SN dysfunction in schizophrenia

2.1 Structural deficits in the SN

The bulk of evidence indicating a role for the SN in the pathophysiology of schizophrenia comes from structural MRI studies. Voxel-based techniques such s voxel-based morphometry (VBM) make it possible to search the entire brain to identify localized differences between patients and controls. Meta-analytic

techniques, such as the activation likelihood procedure, make it possible to synthesize the evidence from multiple investigations. Meta-analyses of studies examining regional differences between patients with schizophrenia and healthy controls have consistently identified several regions and of these, the insula shows the most consistent grey matter reduction in patients(26, 2836). Insula reduction has been identified in all of the meta-analyses irrespective of the duration of illness. ACC is the next most consistent site with GM reductions, followed by superior temporal gyrus. Interestingly, the insular cluster extends to the inferior frontal gyrus anteriorly in a number of these meta-analyses (28, 29, 35) and to the superior temporal gyrus posteriorly in some (31). Less consistent changes were notable in subcortical structures such as the caudate, amygdala and the thalamus. It is important to note that the remarkable consistency is, at least in part, due to the significant overlap in the studies included in these meta-analyses. Nevertheless, each of these meta-analyses focused on identifying studies that undertook a whole brain search without a priori assumptions regarding the loci of GM change in schizophrenia. A summary of these studies has been presented in Table 1,

emphasizing the emergence of the SN nodes. The coordinates identified from these meta-analyses are plotted in Supplementary Material S1.

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Study

Number of studies
29

Bora 2011a (29) Bora 2011a (29) Bora 2011b (28) Chan 2011 (37) Chan 2011 (37) Ellison-Wright 31 2008 (31) Ellison-Wright 31 2008 (31) Ellison-Wright 32 2010 (32) Fornito 33 2009 (33) Fusar-Poli 2011 26 34 (26), 2012 (34) 35 Glahn 2008 (35)
36 37 37 28 29

12 39 49 19 14 20

Number of Patients / Controls 359/421 1719/1851 1999/2180 808/856 566/608 809/798

Contrast

Regions with GM reduction in patients

Comments

SCZ vs. HC SCZ vs. HC SCZ vs. HC Chronic SCZ vs. HC FEP vs HC Chronic SCZ vs. HC

Left frontoinsular cortex, bilateral ACC, bilateral STG Bilateral insula / IFG, left STG, bilateral ACC and dorsomedial frontal regions Bilateral insula/inferior frontal, Bilateral thalamus, Bilateral ACC/medial frontal Bilateral insula, left IFG, left ACC, bilateral amygdala, right STG, left thalamus Bilateral insula, left STG, left amygdala, right IFG, right cingulate gyrus, Bilateral insula, bilateral ACC the left IFG & middle frontal gyrus, left fusiform gyrus, right superior/middle temporal gyrus, left uncus/amygdala, right hippocampus Bilateral uncus/amygdala, bilateral insula, bilateral caudate, bilateral inferior frontal gyrus, left postcentral gyrus. Bilateral insula, left ACC, left thalamus, bilateral medial frontal gyrus Bilateral insula, bilateral ACC, left PCC/precuneus, left amygdala/PHG, left fusiform Left insula, left ACC, right STG, cerebellum Bilateral insula, ACC (ventral, dorsa and subgenual), left PHG, thalamus, left postcentral gyrus, left MFG Bilateral caudate, bilateral insula, right MFG, right STG, Bilateral insula, left MFG and ACC, bilateral STG, right IFG, left PHG/amygdala.

SDM: Only samples with <60% males were included SDM: Only samples with >60% males were included SDM GingerALE Foci >500mm3 shown in the table GingerALE Foci >500mm3 shown in the table ALE approach: GM increases were reported in left putamen, right SFG, right fusiform. ALE approach: GM increases were also reported in bilateral putamen ALE approach GingerALE Foci >500mm3 shown in the table SDM GingerALE Only the foci >400mm3 were reported GingerALE Foci >500mm3 shown in the table GingerALE Foci >500mm3 shown in the table

7 42 37 8 31

170/188 2058/2131 1646/1690 206/202 1195/1262

FEP vs. HC SCZ vs. HC SCZ vs. HC Neuroleptic nave FEP vs. HC SCZ vs. HC

Leung 2011 (36) Leung 2011 (36)

36

6 9

162/165 336/484

Neuroleptic nave FEP vs HC Neuroleptic treated FEP vs.HC

Table 1: Meta-analyses on voxel based morphometric studies highlighting the consistency of structural deficits in the Salience Network when patients with schizophrenia are compared with healthy controls. SCZ: Mixed samples of patients with variable duration of established schizophrenia FEP: First episode psychosis HC: Healthy controls ACC: Anterior cingulate cortex IFG: Inferior frontal gyrus STG: Superior temporal gyrus PCC: posterior cingulate cortex PHG: Parahippocampal gyrus ALE: Activation Likelihood Estimation SDM: Signed Differential Mapping

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(26) (28) (29) (30) (31) (32) (33) (34) (35) (36) (37)

Fusar-Poli, P.; Radua, J.; McGuire, P.; Stefan, B. Schizophr Bull 2011; epub doi: 10.1093/schbul/sbr134. Bora, E.; Fornito, A.; Radua, J.; Walterfang, M.; Seal, M.; Wood, S. J.; Ycel, M.; Velakoulis, D.; Pantelis, C. Schizophr. Res. 2011, 127, 4657. Bora, E.; Fornito, A.; Ycel, M.; Pantelis, C. Psychological Medicine 2011, FirstView, 113. Chan, R. C. K.; Di, X.; McAlonan, G. M.; Gong, Q. Schizophr Bull 2011, 37, 177188. Ellison-Wright, I.; Glahn, D. C.; Laird, A. R.; Thelen, S. M.; Bullmore, E. Am J Psychiatry 2008, 165, 10151023. Ellison-Wright, I.; Bullmore, E. Schizophr. Res 2010, 117, 112. Fornito, A.; Ycel, M.; Patti, J.; Wood, S. J.; Pantelis, C. Schizophr. Res 2009, 108, 104113. Fusar-Poli, P.; Smieskova, R.; Serafini, G.; Politi, P.; Borgwardt, S. World Journal of Biological Psychiatry 2012, 110. Glahn, D. C.; Laird, A. R.; Ellison-Wright, I.; Thelen, S. M.; Robinson, J. L.; Lancaster, J. L.; Bullmore, E.; Fox, P. T. Biological Psychiatry 2008, 64, 774781. Leung, M.; Cheung, C.; Yu, K.; Yip, B.; Sham, P.; Li, Q.; Chua, S.; McAlonan, G. Schizophr Bull 2009, sbp099. Chan, R. C. K.; Di, X.; McAlonan, G. M.; Gong, Q. Schizophr Bull 2009, sbp073.

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The prominence of the structural deficits in the insula noted using VBM studies has been further clarified using a number of region-of-interest studies that specifically focus on the insula. A meta-analysis of ROI studies focussing on the insula was recently published(38). The pooled results from fifteen studies that met the inclusion criteria (n = 945) showed a medium-sized reduction of bilateral insula in people with schizophrenia (either chronic or first episode), with reductions in anterior insula showing considerably larger effect sizes than the reductions in posterior insula, suggesting a regional anterior-posterior anatomical distinction. Surface based morphometric studies suggest that the GM deficits seen in the SN result from a combination of cortical thinning and reduced surface area (39, 40). In addition, insula shows a significant reduction in the degree of cortical gyrification that is not seen in the dACC(41).

To determine which of the regional GM deficits in schizophrenia have a high probability of co-occurrence in a given subject, a network analysis aimed on voxelbased morphometry (VBM) studies was performed by Glahn et al(35). Interestingly, insula and dACC changes loaded onto separate networks. Thus, despite the evidence from functional imaging studies indicating that insula and dACC are nodes of the SN (2,3), the evidence for structural studies suggest that these two regions have somewhat different patterns of shared structural variance with other brain regions. Insofar as shared structural variance might indicate shared developmental processes, this evidence suggests that there are appreciable difference sin developmental influences acting on these two regions. But given the intricate structural and functional connectivity between these two regions, it is possible that a direct relationship exists between the neuronal integrity of the ACC and the structural deficits in the anterior insula in schizophrenia. We investigated this issue (unpublished data) by studying the correlation between n-acetyl aspartate (NAA) levels reflecting neuronal integrity in the ACC and the GM thickness in the anterior insula in a sample of medicated male patients with established schizophrenia (n= 16; mean(SD) age in years = 23.1(5.1); mean(SD) duration of illness in years =2.2(1.5)) and healthy controls (n= 16; mean(SD) age = 24.5(5.4)). We observed a significant linear correlation (adjusted for age and global cortical thickness) between reduced NAA levels in the ACC and cortical thickness of the right anterior insula in patients (r=0.57, p=0.03, df=12) but not in healthy controls (r=-0.26, p=0.37, df=12). Patients also showed a significant reduction in the NAA concentration in ACC (Cohens d = 0.79, F=5.56, p=0.025) and right anterior insular thickness (Cohens d = -0.61, F=4.49, p=0.04). This observation, though limited to a small sample of male subjects,
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suggests that in schizophrenia ACC and insular defects are likely to reflect a shared pathological mechanism.

2.2 Functional deficits in the SN The SNs putative proximal salience function dictates that it recruits functional systems in a contextually- and temporally-relevant manner. SN activity has largely been studied in relation to two other fundamental distributed networks underpinning contrasting modes of brain function(42) ; DMN regions including medial prefrontal cortex, posterior cingulate cortex, bilateral angular gyrus and medial temporal lobe are preferentially active when attention is internally focused; by contrast, the central executive network (CEN), which comprises bilateral dorsolateral prefrontal and parietal cortex, subserves environmentally-focused information processing. Grangercausality analysis of temporal dynamics in these three networks (across multiple tasks) has revealed that BOLD activity in SN precedes and predicts activity in both DMN and CEN, implying that the SN coordinates multi-network activity(9). Since connectivity measures which use BOLD information directly rather than modelling underlying neuronal states are potentially confounded by inter-region variation in vascularisation and/or neurovascular coupling, these findings must be treated with fair caution until confirmed. However, the recent application of temporal Independent Component Analysis (ICA) to magnetoencephalographic data (43, 44) holds promise as resulting connectivity measures are not contaminated by these inter-region haemodynamic differences and also potentially shed light onto the involvement of oscillatory processes in network coordination.

Dysfunction to this network-coordination system feasibly underlies wide-ranging aspects of psychopathology (1, 45); its discussion in relation to schizophrenia forms the basis of later sections of this article. Functional deficits within SN nodes are well studied in schizophrenia. Consistent with the notion that SN fundamentally coordinates contextually-relevant brain activity, SN dysfunction in schizophrenia has been reported in diverse cognitive settings. Fusion ICA on a dataset involving processing of sparse somatosensory events interspersed with long rest periods, showed that SN activity was less closely related to that of perceptual regions and less negatively related with DMN activity in individuals with schizophrenia compared to matched control subjects(46). A further analysis of the same data, which assessed maximal-lagged temporal correlations between timecourses of independent

components, demonstrated that individuals with schizophrenia exhibit reduced

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connectivity both within the SN and between the SN and DMN(47), implying that both the functional integrity of the network and its relation to other networks is disturbed in the disorder. The hypothesis of reduced SN functional integrity is further supported by findings of reduced functional connectivity in schizophrenia compared to controls between a cingulate-cortex seed and anterior insula (as well as pre-supplementary motor area and thalamic regions) during volitional eye saccades(48), and between dACC and bilateral putamen during rest (49). However, within-network

disconnectivity in the SN is not unequivocally apparent in schizophrenia. Restingstate SN connectivity with a fronto-insular seed was recently reported to be unaffected by schizophrenia, despite significant connectivity reductions in both DMN and CEN(50), though SN disconnectivity becomes apparent in larger samples(51). A recent fMRI study investigating the modulation of intra- and inter-network connectivity by working memory load in individuals with schizophrenia and matched controls reported that increased working memory load led to increased anticorrelation between SN and DMN, and increased correlation between SN and CEN in both groups. Nevertheless, schizophrenia-related dysconnectivity in these measures was observed to be similar in magnitude across rest and all working memory loads(52). Furthermore, reduced SN activation and reduced DMN deactivation along with impaired anti-correlation between DMN and CEN appears to be a prominent abnormality during task performance even 1 year after remission of first episode of schizophrenia(53). Overall, these studies suggest that altered SN connectivity with other cortical networks is a stable characteristic of the pathophysiology of schizophrenia. The observation of within network dysconnectivity may require taskprocessing experiments, while subcortical-SN dysconnectivity may be more apparent at resting state. It is possible that in addition to task-related differences, some of the variations in the localization of the SN connectivity disturbance could also be related to sample heterogeneity. Systematic examination of both task-related and samplerelated effects on a broad range of SN connectivity measures in schizophrenia is required to clarify this issue.

SN functional abnormality can also be inferred from unconventional recruitment of large-scale distributed networks in schizophrenia. For instance, Hasenkamp et al.(54) reported just 5% overlap between patient and control group activation maps assessing the main effects of task during a simple visual target detection paradigm. Task-related activation in healthy individuals was focused in fronto-insular and executive network regions, and DMN regions were strongly deactivated. In patients with schizophrenia, activation was restricted to dorsolateral prefrontal and parietal
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cortices and there was diminished DMN deactivation. Similarly, in a dichotic auditory cognitive task individuals with schizophrenia exhibited decreased upregulation of an executive network including dACC and anterior insula, and attenuated

downregulation of DMN regions as compared to controls(55). These results emphasise that contextually-relevant brain function is contingent not just on the recruitment of task-relevant regions but also the controlled dampening of the action of potentially disruptive systems, both of which are ascribed to the dynamic switching function of the SN. This is further supported by the observation that in healthy controls SN connectivity at rest predicts working memory performance(49). In contrast, in patients it does not but rather is negatively correlated with the severity of negative symptoms in these individuals(49). Such findings support the hypothesis that SN connectivity disturbance is a pathophysiological mechanism of schizophrenia.

Investigating schizophrenia-related disturbance to cerebral function is often confounded by systematic differences between patients and controls in task performance. Although studying resting-state activity arguably lessens these between-group effects, it can be contended that resting-state experiments merely employ a poorly-controlled cognitive task. In contrast, single-pulse transcranial magnetic stimulation (spTMS), by which localised neuronal populations are directly activated, enables the investigation of haemodynamic responses in a nonconfounded manner. It has been shown that sp-TMS of precentral gyrus induced significant reductions in haemodynamic peak amplitude in schizophrenia compared to controls in regions including thalamus and anterior insula, and further that thalamo-insular functional connectivity was reduced in patients(56); importantly this suggests that these and other SN functional deficits are not wholly due to impaired task performance in individuals with schizophrenia.

Overall, there is strong evidence for SN structural and functional abnormality in schizophrenia. The next step of directly mapping structure to function is dependent on the convergence of distinct lines of evidence. An initial multimodal investigation of SN abnormality in schizophrenia has produced promising findings suggesting that SN functional aberrance is structurally determined. Explicit co-examination of oscillatory and GM disturbances in patients with schizophrenia revealed that eventrelated phase resetting of frontal theta oscillations is less efficient in patients with reduced SN thickness(57). This finding provides a link between the structural and

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functional deficits in the SN and underlines the potential worth of bringing together further multimodal findings to delineate the SN dysfunction in schizophrenia. 3. SN dysfunction and psychotic symptoms

3.1 Relationship to prodromal symptoms

Inappropriate generation of proximal salience could be conceived as a central feature in the generation of the variety of symptoms that characterize prodromal stages of schizophrenia. The early stage of this illness is often marked by the presence of so called basic symptoms that includes several perceptual and cognitive disturbances such as disturbances in visual perception of self and others, seeing special meanings in advertisements, other peoples conversations, heightened sensitivity to

light/acoustic stimuli, distraction by irrelevant stimuli, experiencing unusual sounds (e.g. banging, clicking, hissing) and feeling that parts of body are changed in some way(58). A direct causal association between SN dysfunction and prodromal symptoms are yet to be investigated, but a number of observations suggest that inappropriate proximal salience could provide meaningful explanations of most of the clinical features seen in patients with a pre-psychotic mental state.

One of the typical features of this prodromal state in schizophrenia is a subjective feeling of uncertainty or perplexity where spontaneous grasp of commonsensical meanings appear reduced(59). In social neuroscience, uncertainty is defined as the inability to predict an outcome(60). It is the degree to which past and present states are known and the predictive models are utilized when faced with the objects of the world. Anterior insula plays a crucial role in both the subjective feeling state of uncertainty and decision-making under uncertainty (6062). The prominent insular structural deficits noted during prodromal state (26, 63, 64) indicate that inappropriate proximal salience may be associated with the perplexity noted during the prodrome, though this is not systematically examined to date.

Failure of appropriate use of the predictive models as a result of SN dysfunction can form the basis of several perceptual distortions seen in the early stages. In healthy volunteers, aFI plays an important role in filling-in missing data using a priori predictions to create seemingly uninterrupted percepts(65, 66). Irrespective of the modality of the presented stimulus aFI is involved in the expectancy related preparatory modulation of corresponding primary sensory cortices (67). A failure to
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utilize predictive models and generate adequate proximal salience required for sense perception could explain disturbances in experiencing ones surroundings and social milieu. In the absence of sufficient access to predictive models, an individual may resort to over-reliance on the sensory evidence in order to create a percept. In fact, such an overreliance on sensory evidence has been demonstrated in patients when faced with complex social situations(68). Proximal salience in this case may be inappropriately assigned to the primary sensory regions of the brain in a nonselective fashion, resulting in increased distractibility, changes in the perception of the intensity/quality of the objects in ones environment and at times apparently phantom percepts (e.g. elementary hallucinations such as flashes of light, hissing/banging noises)(69).

A characteristic feature of schizophrenia that has historically shaped the diagnostic criteria for the illness is an altered self-other boundary(70). Several neuroimaging studies have pointed to the anterior insula being the representational cortex for the sense of self (13, 71), tightly linked to the interoceptive awareness created by an inflow of information regarding ones bodily state(72). The integration of such information in the aFI also results in accurate emotional appraisal(73) and a sense of presence(74), both of which are altered in early stages of schizophrenia. Symptoms such as depersonalization (feeling detached as if ones body is unreal), body perception disturbances (known as coenesthetic phenomena) and a decreased capacity to distinguish emotions are likely to be linked to the dysfunctional integration of interoceptive awareness arising from aFI dysfunction in schizophrenia.

3.2 Relationship to symptoms in established illness

In its established phase (i.e. either acute episodes or chronic illness), several overlapping clinical syndromes present in variable degree in individual patients characterize schizophrenia. This includes reality distortion (hallucination and delusions), disorganisation of speech/behaviour and psychomotor poverty(75, 76). Depressive symptoms and psychomotor excitation are also notable features in a substantial number of patients(77).

One of the most common reported symptoms in schizophrenia is auditory hallucination (AH). Numerous structural and fMRI studies have investigated the neural correlates of AH in schizophrenia. Using a meta-analytic approach applied to
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VBM studies, we earlier reported that the severity of AH is higher in patients who have a greater reduction of GM in the left aFI and right superior temporal cortex (78). Jardri et al.(79) undertook a meta-analysis of functional studies (fMRI and PET) investigating actively hallucinating individuals and noted a predominant locus of activation in the left aFI. This observation has been replicated by using a different meta-analytic approach in an extended number of studies(80). Further, in a sample of clinically stable medicated patients with chronic schizophrenia we observed an inverse relationship between GM volume in the SN nodes (anterior insula and dACC) and the severity of reality distortion (hallucinations and delusions)(81). Functional connectivity analysis suggests that the severity of hallucinations is directly related to the reduced connectivity within the SN

Epidemiological surveys of schizophrenia identify loss of insight as a predominant feature of the illness(82). While consistent neural correlates of poor insight in schizophrenia are still elusive, in a region-of-interest study, we observed that reduced grey and white matter in the right posterior insula were associated with a prominent lack of insight(83). It is important to note that posterior insula is not generally considered to be a part of the SN; posterior insula may in fact participate in an extended interoceptive rather than a task-positive network (84, 85). Nevertheless as posterior insula is considered to be a crucial relay centre of interoceptive signals that are integrated with the exteroceptive awareness in the representational cortex of anterior insula(13), dysfunctional connections between these two nodes may contribute to both poor interoceptive awareness and reduced insight.

Disordered thought process expressed during speech is a prominent feature of schizophrenia(86) . Thought disorders include impoverished speech output and defects in the goal-driven organization of the expressed language. Despite its prominence as one of the characteristic features of the psychotic process, surprisingly few studies have explored the relationship between brain mechanisms and thought disorganisation. A crucial limiting factor has been the difficulty in quantifying the severity of thought disorder during clinical interview(87). Scales that utilize spontaneous thought generation circumvent this problem(88). Earlier PET studies indicated a role for both ACC and insula in thought disorder(89). A positive relationship between rCBF in the aFI and ACC and the severity of thought disorder was later reported by Horn et al.(90) and Lahti et al(91).

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It is important to consider how this predominant language function fits in the context of SN function. SN has been implicated in having a prominent role in moment-tomoment adjustments during task performance(92) and inhibition of contextually inappropriate responses(93). Violation of expectancies that occur during such task performances activate the SN in the same manner as the external stimuli with predictive surprise that generate stimulus-response discrepancies. When

orchestrating the task of speech production, the SN may facilitate brain states that reduce the action-outcome discrepancies, by enabling modification in the articulatory plan or the motor speech production. A failure to do so may be expressed as

syntactical errors, perseverative responses and a drift from goal-driven conversation seen in patients with schizophrenia. Several studies involving patients with prominent speech production difficulties (aphasias) implicate the importance of aFI in articulatory plan (94, 95) and facilitating access to stored lexical models essential for normal speech production (96, 97). Impoverished speech observed in social context in schizophrenia could be ascribed to a significant failure of proximal salience generation in response to social cues. In the absence of studies that investigate this issue directly, the observation of ACC lesions in individuals who show extreme lack of motivation, apathy and mutism(98, 99) support the speculation that SN dysfunction could underlie psychomotor poverty, at least in some patients with schizophrenia.

The role of SN dysfunction is being increasingly appreciated in the pathogenesis of a depressive mental state. aFI is a strategically located hub with functional connectivity to both a cognitive control loop (the SN) and an affective loop that includes subgenual ACC, amygdala and other limbic structures(7, 100, 101). Meta-analysis of neural response to negatively valenced affective stimuli showed a greater response in the amygdala and the SN and a lower response in dorso-lateral prefrontal cortex and dorsal striatum in clinically depressed individuals(102). Concomitant observation of higher thalamic pulvinar activity at baseline in depression suggests that excessive thalamo-amygdalo-insular excitation may drive inappropriate generation of proximal salience, combined with a failure to update the predictions concerning the negative valence of the stimuli that may be represented in the DLPFC(102). This heightened SN activity for aversive stimuli in a depressed mood state is also notable in individuals without clinical depressive disorder. Increased SN activity was observed specifically when unfair monetary offers were made to healthy volunteers with induced sad mood(103). In this case, the heightened insular activation mediated rejection of the unfair offers, suggesting that insular activity may mediate decisionmaking biases seen in depression. Interestingly, antidepressants normalize both the
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reduced DLPFC activation and the increased SN activation(104), thus restoring the emotional processing deficits associated with depression. To our knowledge, the relationship between SN dysfunction and depressive symptoms seen in

schizophrenia has not ben investigated.

In summary, the present model for SN dysfunction in schizophrenia could potentially explain several clinical features of this illness. Whilst some of these associations have been consistently noted (e.g. reality distortion and SN structural deficits, thought disorder and rCBF in the insula), others are yet to be established. Though it is likely that other brain regions also play an important role in the generation of many of the symptoms of schizophrenia, cardinal role of the SN in integrating perception of the external and internal world and in facilitating appropriate responses endows it with the potential to play a major role in a wide range of symptoms seen in patients with schizophrenia. The strong evidence demonstrating that SN is a consistent site of structural abnormality in schizophrenia, together with the specific evidence for an association between structural abnormality in the insula and key symptoms such as hallucinations and formal thought disorders, suggest that SN is likely to be on the causal pathway for expression of many of the symptoms of schizophrenia.

4. Putative schizophrenia risk factors affect the SN

The most strongly established risk factor for developing schizophrenia is the presence of a familial history of schizophrenia(105). In a coordinates based metaanalysis of VBM studies, we observed that the structural deficits of the insula and ACC were more likely to be seen in patients who expressed clinical features of schizophrenia than in non-psychotic high-risk relatives who carry a genetic diathesis of the illness(106). By contrast, genetic diathesis is associated with GM deficits in amygdala, putamen and thalamus. Though these results suggest that environmental insults could be associated with the structural deficits in the SN seen in schizophrenia, this does not rule out the possibility that candidate genes could exert an influence on the structure of the SN. Further, it is important to note that imaging genetics using VBM approach are likely to be confounded by the composite nature of the GM volume measured using VBM. Examining the distinct components of thickness and area in relation to candidate genes is more likely to be fruitful. One such candidate gene is Disrupted-in-schizophrenia 1 (DISC1), which regulates several aspects of corticogenesis (107, 108). Multiple imaging studies have demonstrated both structural and functional changes in Ser homozygotes that are
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relevant to the pathophysiology of psychotic disorders(109111). In a sample of 23 patients with psychosis (schizophrenia or bipolar disorder) and 22 healthy controls, we observed that patients who were Ser homozygotes for Ser704Cys DISC-1 polymorphism had a significant reduction in the thickness of ACC/Insula compared to Ser homozygous controls(112). In contrast, no significant difference in the cortical thickness was observed in Cys carriers(112). The polymorphism was not associated with effects on the cortical surface area of ACC/Insula. This suggests that genetic factors may confer a degree of vulnerability to the SN, making it prone for further influence from environmental factors.

Prominent environmental factors known to be associated with an increase risk of schizophrenia include obstetric complications in the mother, exposure to

psychoactive substances such as cannabis, social adversity associated with immigration/urbanicity(105) and more recently, accumulating evidence suggests that maternal infections associated with a systemic inflammatory response may confer a risk(113). Interestingly a number of these factors affect the structure/function of the SN either directly or indirectly.

Epidemiological studies consistently show a relationship between being an immigrant and having a higher risk of schizophrenia(105). While the exact mechanism of this association is still unclear, social adversity in an unpredictable environment is highlighted as an important mediator of this relationship(114). Young adolescents who show a higher cortisol response to experimentally induced social stress exhibit a higher functional connectivity within the SN identified using ICA of resting fMRI(115). Events that threaten social rank consistently activate anterior insula, with an associated bias towards excessive activity in the primary sensory cortex(116). Such preferential activation of the SN may have an adaptive function, driving the reallocation of neural resources towards a stimulus evaluation mode(117). But repeated exposures to stressors may have long lasting effects on the SN. Healthy volunteers with higher exposure to chronic subjective stress (cumulative adversity) have reduced volumes in several SN nodes including right anterior insula and ACC(118). In particular, exposure to recent life events has a direct impact on insular volume while a history of lifetime trauma correlated with reduced ACC volumes(118). Urban upbringing, which is also associated with an elevated risk of

schizophrenia(105), is related to higher ACC activation during stressful cognitive tasks (an arithmetic task combined with regular disapproving feedback)(119). In summary, these neuroimaging observations indicate that social adversity can induce
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a dysfunctional SN response to stress. Repeated exposure to stressful social events are likely to be associated with structural changes in the SN along with an excessive engagement of the SN when faced with stress.

Cannabis has a well-known association with the risk of schizophrenia, especially if the exposure begins at adolescence and continues for a long duration(120). VBM studies seeking anatomical changes in cannabis users have produced inconsistent results(121). There is some evidence to suggest that specific structural phenotypes such as cortical thickness show higher sensitivity to cannabis exposure(122). Adolescents using marijuana have reduced bilateral insular thickness compared to non-smoking controls(123). Patients with schizophrenia who continue to smoke cannabis show progressive cortical thinning in the ACC compared to patients who do not use cannabis(124). fMRI studies have consistently implicated abnormalities of the SN nodes in cannabis users. During an auditory attention task requiring cognitive control, smoking marijuana induced higher rCBF to the SN but reduced rCBF to auditory cortex when compared to placebo(125, 126). This pattern was also noted using resting arterial spin labeling method wherein an acute challenge with THC, the active ingredient of cannabis, results in increased perfusion in the SN even when not performing external tasks(127). THC also increased the amplitude of fluctuations in resting-state functional MRI signal after THC administration in the insula(127). By contrast, heavy marijuana smokers show a reduction in insular rCBF at resting state after short abstinence when compared to non-smoking controls. A sample of chronic users who were abstinent for a short period showed hypoactivity in the anterior cingulate (ACC) and right insula during an error awareness task(128). Task performance in cannabis users improved with higher levels of activation in these regions, suggesting that SN deficits may mediate behavioural deficits in chronic cannabis users(128). Taken together these observations suggest that recurrent

exposure to cannabis could alter the normal physiological function of the SN, with heavy use during adolescence being associated with reduced cortical thickness in the insula. Prenatal infections such as influenza could affect the structure of murine neocortex by affecting secretory proteins such as reelin which are essential for a normal lamination of brain(129). Pregnant rhesus monkeys infected with influenza during early third trimester give birth to offspring that show a diffuse reduction in cortical GM, including bilateral cingulate and right insular cortices(130). Perinatal complications

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are associated with insular structural defects in human infants too. Between ages 7 and 10, preterm children show reduced cortical thickness in the right anterior insula and the ACC compared to term-born children(131). This effect is also notable between ages 14-15, who show significant GM reduction in bilateral insula when compared to term born adolescents(132). Among individuals aged between 13 to 22 years and considered to be at risk for psychosis due to cognitive reasons, low birthweight is associated with reduced GM density in the left insula and temporal cortex(133). Human neuroimaging studies focusing on inferior frontal cortex suggest that in both healthy volunteers and patients with schizophrenia, perinatal birth complications are associated with altered gyrification rather than cortical thickness (134, 135). While the effect of obstetric events on insula/ACC morphology in schizophrenia is yet to be studied, it is important to note that unbiased whole brain studies in schizophrenia implicate the aFI as the cortical region with the most prominent reduction in gyrification(41, 136). Thus events such as obstetric complications that affect normal neurodevelopment and increase the risk of schizophrenia could exert a significant influence on the structure of the SN. Structural and functional maturation of aFI pathways, especially the SN, is considered to be critical for the development of cognitive control mechanism through adolescence(11). In fact, the developmental changes that occur in the SN appears to be the best predictor of brain functional connectivity maturation(137). Atypical maturation of this network is likely to have the greatest functional impact at the developmental stage when its functions normally emerge i.e. during adolescence. This notion is

consistent with the epidemiological observation that the onset of schizophrenia is usually around late adolescence(138).

5. Neurochemical basis of SN dysfunction

At present, the neurochemical basis of the several crucial functions of the SN in relation to proximal salience is unknown. Given the complexity of the functions ascribed to the SN, it is reasonable to expect significant modulatory role for a number of key neurotransmitters such as dopamine, glutamate, GABA, noradrenaline and acetylcholine. In the context of the pathophysiology of schizophrenia, an important issue is to understand the neurochemical basis of the SN dysfunction in relation to psychotic symptoms.

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Numerous observations provide circumstantial evidence for the role of dopaminergic system in the physiology of the SN (for a review, see Palaniyappan & Liddle(1)). More direct evidence comes from pharmaco-fMRI studies wherein dopaminergic drugs are administered to study changes in functional connectivity. D2/D3 agonist pramipexole increases the connectivity between ventral striatum (VS) and the anterior insula when anticipating monetary rewards(139). Similar effects are observed when a single dose of 100mg levodopa is administered to healthy volunteers. In this case, levodopa increases the resting state functional connectivity between the VS and the SN(140). On the other hand, 3mg of haloperidol reduces the resting state connectivity between the VS and the SN(140). Consistent with the later observation, D2 antagonist sulpride also reduces the activity of both VS and ACC in response to rewarding stimuli(141). These observations suggest that dopamine has a crucial role in the interaction between the striatum and the SN.

Given the importance of SN in enabling stimulusresponse associations, a crucial role for GABA in the physiology of SN is highly likely. Several lines of evidence for this notion come from animal studies. In midbrain, GABA interneurons code for the expectancy in associative learning paradigms. GABAergic neurons counteract excitatory drive from primary reward when the reward is expected(142). In the absence of such GABAergic modulation, more frequent dopaminergic bursts are observed(143) with a faster associative learning and a tendency to have higher risk preference(144). Cytoarchitectural studies of insula suggest an abundance of GABA interneurons that receive direct input from the midbrain dopaminergic pathways(145). Disruption of early trophic influence on GABA interneuron development leads to selective loss of parvalbumin containing GABA interneurons in the insula and visual cortex(146)(146)
146

, suggesting that GABA deficits might play a major role in

functional deficits arising from abnormal development of these regions. In human subjects, variations in GABA-RA2 genotype influence insular activation during anticipatory processing(147) highlighting the role of GABA in insular function. Pregabalin, a GABA potentiator, reduces insular activation during anticipatory processing(148), while the benzodiazepine lorazepam reduces insular response to emotional face processing(149). Further, GABA agonist baclofen reduces resting cerebral blood flow to bilateral insula(150) Interestingly, an opposite effect on insular rCBF is noted when NMDA antagonist ketamine is administered in subanaestheic doses(151), indicating that the GABA/Glu coupling potentially mediates the function

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of the aFI. Ketamine, which produces a preferential blockade of the glutamate receptors on the inhibitory GABA interneurons, increases the glutamate turnover in ACC, as evidenced by an increase in glutamine level(152). Further, associative learning mediated by the insula is associated with changes in both the glutamate levels (153, 154) and increased GABAergic (GAD67+) interneuron activity(155). In a meta-analysis of MRS studies in schizophrenia, medial prefrontal cortex (including the ACC) showed significant reduction in glutamate levels but an increase in glutamine concentration(156). It is important to note that most MRS spectra in the studies considered by Marsman et al. (156) did not have sufficient resolution to reliably separate glutamine and glutamate signals. Further, the MRS Glx (glutamate+glutamine) measurements could reflect any of the three (synaptic extracellular, glial or neuronal) compartments of the glutamate/glutamine pool in the brain tissue. This precludes meaningful interpretation of this data in terms of the SN dysfunction in schizophrenia. So far, in vivo measurement of Glu/GABA from the aFI has not been reported in patients with schizophrenia though several studies have highlighted the usefulness of the GABA/Glu quantification from the insula in other disease states, especially fibromyalgia (157159). The most relevant study n this context was carried out on patients with a depressive disorder. Horn et al(160) investigated the relationship between Glx at the ACC and the functional connectivity of the SN and observed a linear relationship in depressed patients, but not in healthy controls. Patients with severe depression also had a significant reduction of Glx concentration. This observation supports the notion that the integrity of SN in schizophrenia could have a similar relationship to Glutamate concentration, though this issue is yet to be investigated. Relative balance between GABA and Glu in the ACC is likely to be important in modulating the BOLD response across both the DMN and task-positive networks(161, 162).

Several other neurotransmitter systems also influence the activity of the SN. Nicotine normalises the ketamine induced increase in the rCBF of the SN(163), suggesting a role for cholinergic transmission. Beta-adrenergic blockade diminishes the

responsiveness of the SN to fear stimuli(117). The degree of regional brain activation in response to a given task and functional connectivity of a region with other nodes is likely to be influenced by interactions among several neurotransmitter systems(164). With a note of caution on the oversimplification of the available evidence, we may assume that dopamine has a crucial role in the interaction of the SN with subcortical sites, whilst the within-network connectivity of the SN and the interaction of the SN

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with other large-scale networks may predominantly depend on the Glu/GABA neurotransmission.

6. SN dysfunction as a therapeutic target

From the numerous studies that are reviewed above, it is evident that the SN dysfunction forms a crucial cog in the wheel of the complex pathophysiological process that results in the expression of several of the psychotic symptoms in schizophrenia. Importantly, pharmacological manipulation of the SN function appears to be a feasible strategy in treating psychotic symptoms. Increasingly it is being realized that drugs targeting a single neurotransmitter system (the so-called magic bullet approach) provide insufficient translational benefit(165). Network

pharmacology, which aims to address large-scale brain network dysfunctions in brain disorders, is proposed as an alternative strategy for drug development(166).

Reorganization of brain networks involves habitual reallocation of neural resources on demand(167). This plasticity of functional networks open the possibility that such reorganization could be achieved, at least in part, through focused cognitive training(168170). This approach has been advocated for anxiety disorders, with specific training approaches proposed to address targeted dysfunctional networks underlying anxiety symptoms(171). Combination of network pharmacology to improve plasticity of connections, along with targeted cognitive training is likely to be a powerful approach to address dysfunctional brain networks. This combined approach can be termed as Brain Network Modulation (BNM), and has a potential to address several of the symptoms of schizophrenia. This is especially important as a number of observations suggest that isolated pharmacological approaches could often elicit compensatory or feedback mechanisms, which either reduce the effectiveness of treatment or cause additional unwanted effects(172).

In schizophrenia targeted cognitive training addressing working memory deficits has been shown to be associated with improved BOLD activation in prefrontal regions(173). One cognitive approach that bears several properties of being a SN oriented training method is mindfulness training(174, 175). Neuroplastic changes in the anterior cingulate cortex and insula has been consistently observed along with changes in other fronto-limbic nodes and default mode network structures (see Holzel et al.(176) for a review). While different degree of mindfulness training are
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present in various psychological therapies and meditations approaches, two crucial components of mindfulness are (1) attention to the present moment instead of delving into memory / mind-wandering and 2) the suspension of cognitive elaboration/appraisal of present perceptions (177). Experienced meditators show stronger functional connectivity between the posterior cingulate (DMN node), dACC (SN node), and dorsolateral prefrontal cortices (CEN node)(178). Several studies indicate that mindfulness practices improve the degree of deactivations seen in cortical midline structures constituting the DMN(179, 180). Mindfulness also increases the BOLD correlation between nodes of the SN and relevant sensory cortex when attending to a stimulus, while increasing the anticorrelation with irrelevant sensory cortices(181). Practicing mindfulness meditation has been shown to increase the recruitment of anterior insula during interoceptive attention, and influence the connectivity between posterior and the anterior insula(182). A reduction in the perception of pain and anxiety through the practice of mindfulness is associated with (1) increased ACC engagement in anticipation of the pain stimulus and (2) reduced lateral prefrontal cortex but increased posterior insula engagement on presentation of the pain stimulus(183). Interestingly, in a large sample of long-

term meditators, pronounced increase in gyrification was noted in the right anterior insula when compared to non-meditators(184), suggesting that recurrent practice of mindfulness based approaches may have a significant effect on both the connectivity and morphology of aFI.

Another approach that bears some promise in manipulating the SN and its interaction with other distributed networks is neurofeedback using realtime fMRI (RtfMRI) or EEG. In realtime fMRI based neurofeedback subjects can be trained to influence the amplitude of fMRI signal from a specifc brain region while receiving operational information about the signal(185). Neurofeedback has been shown to be effective in modulating cortico-subcortical connectivity in patients with Parkinsons disease(186). Both upregulation and downregulation of BOLD activity in several nodes of the SN appears to be possible using this technique in both healthy volunteers(185, 187, 188) and patients with mental disorders(189). Patients with schizophrenia successfully trained in neurofeedback paradigms and the potential of this technique in addressing symptoms of psychosis is being increasingly appreciated(190). In a small sample of patients with schizophrenia (n=9), volitional control of the hemodynamic response in bilateral anterior insula was achieved using neurofeedback after 2-weeks of training(191). On learning insular self-regulation, patients showed an improved accuracy in recognizing faces showing the emotion of disgust. This improvement
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positively correlated with the capacity to self-regulate right anterior insula. RtfMRI training was also associated with an increase in the effective connectivity among insula, amygdala and mPFC and an overall increase in the causal inflow density to the ACC(191).

It is important to note that there is no randomized trial evidence for neurofeedback in schizophrenia. While mindfulness based approaches have been shown to have certain positive effects on psychotic symptoms, the clinical use of this technique is far from established. Though current understanding of synaptic mechanisms suggests that modulation of neurotransmitters could influences neuronal network plasticity(192, 193), to our knowledge, there have been no trials of Brain Network Modulation (combined cognitive training approaches and pharmacological treatments) in psychosis. As we understand more about brain states and their alterations in schizophrenia, clinical utility of these approaches could become readily achievable. A crucial next step is to characterize the neurochemical basis of the proximal salience and SN dysfunction, and evaluate the proof for the concept of BNM approach of neural plasticity. The concept of SN dysfunction promises a viable target for BNM approaches that can guide treatment developments in the near future.
Figure 1: A speculative model for targeting dysfunctional SN in schizophrenia. A. Subcortical-SN connectivity likely to be predominantly dopaminergic and affected by antipsychotics. B. Within SN connectivity and C. SN-CEN / SN-DMN connectivity are likely to be predominantly GABA/glutamatergic. Brain Network Modulation (indicated by plus sign) can target the within-network and between-networks dysfunction through a combination of pharmacological and cognitive approaches. SN: Salience Network, CEN: Central Executive Network, DMN: Default Mode Network

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Conclusion Current therapies produce relatively limited improvement on long-term outcome for schizophrenia. The evidence that the pathophysiology of the disorder entails subtle but consistent structural abnormalities of cortex, especially in brain regions comprising the SN, suggests that improvement on long-term outcome will require therapies that can alleviate the effects of structural abnormality. The

accumulating evidence indicating that various psychological therapies can produce increases in cortical grey matter and/or improved function of SN demonstrate that plasticity exists and suggest the that structural lesions are that not necessarily and

irreversible. Furthermore,

preliminary

evidence

GABAergic

glutamatergic abnormalities might be involved in developmental deficits in the nodes of the SN suggests appropriate modulation of GABAergic and glutamatergic transmission via pharmacological treatment might act synergistically with

neuropsychological strategies to produce enduring changes in structure and function of the SN leading to substantial improvement in long term outcome of schizophrenia.

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Supportive/Supplementary Material:

S1: Illustration of regions of significantly decreased grey matter derived from several metaanalyses of VBM studies of first-episode schizophrenia [axial view with red clusters] and samples that included a range of episodes [coronal view with blue-green clusters]. All reported coordinates were included with no prespecified inclusion threshold. Smoothing was performed with a 20-mm full-width at half-maximum Gaussian kernel. The details of individual meta-analytic studies are reported in Table 1. Insula and anterior cingulate cortex (ACC) are encircled. Slices are selected for the best visual display of the insula and ACC nodes. The inflated co-ordinate maps are overlaid on a single subject T1 image provided with MRICron software. .

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