Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction

Palaniyappan, Lena; Liddle, Peter F.

doi:10.1503/jpn.100176

Cited by 496 publications

(494 citation statements)

References 152 publications

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“…In contrast, cannabidiol (CBD), another major ingredient may have anxiolytic Fusar-Poli et al, 2009) and antipsychotic-like effects ) and may oppose the neural effects of delta-9-THC and block the psychotogenic Morgan and Curran, 2008) and cognitive (Morgan et al, 2010a(Morgan et al, , 2010b effects of delta-9-THC. We have recently reported that the induction of psychotic symptoms by delta-9-THC may be related to its effects on the striatum and the prefrontal cortex, integral components of a network of brain areas involved in processing of salient information (Bhattacharyya et al, 2012c), consistent with emerging evidence regarding the role of aberrant salience attribution in psychosis (Jensen and Kapur, 2009;Palaniyappan and Liddle, 2012). Furthermore, we showed that CBD and delta-9-THC had opposite effects on the striatum, the hippocampus, and the inferior frontal gyrus, which are key components of a network of brain areas involved in the processing of salience (Rubia et al, 2007;Strange and Dolan, 2001;Zink et al, 2006).…”

Section: Introductionsupporting

confidence: 67%

“…The antagonistic effects of delta-9-THC and CBD were evident on the connectivity of the inferior frontal gyrus, striatum, and hippocampus with other brain areas known to be involved in the processing of salience, such as the anterior cingulate/medial prefrontal cortex, parahippocampal gyrus, and ventral striatum (Palaniyappan and Liddle, 2012). This is consistent with differential modulation of both the processing of salient information in humans and its underlying neural substrates by delta-9-THC and CBD, which has been demonstrated in our previous study shows that connectivity of the dorsostriatal seed cluster with the inferior frontal gyrus (y axis; arbitrary units) in (a) was attenuated by delta-9-THC but augmented by CBD.…”

Section: Discussionmentioning

confidence: 99%

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Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

Bhattacharyya

Falkenberg

Martín‐Santos

et al. 2014

Neuropsychopharmacol

105

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There is now considerable evidence to support the hypothesis that psychotic symptoms are the result of abnormal salience attribution, and that the attribution of salience is largely mediated through the prefrontal cortex, the striatum, and the hippocampus. Although these areas show differential activation under the influence of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), the two major derivatives of cannabis sativa, little is known about the effects of these cannabinoids on the functional connectivity between these regions. We investigated this in healthy occasional cannabis users by employing event-related functional magnetic resonance imaging (fMRI) following oral administration of delta-9-THC, CBD, or a placebo capsule. Employing a seed cluster-based functional connectivity analysis that involved using the average time series from each seed cluster for a whole-brain correlational analysis, we investigated the effect of drug condition on functional connectivity between the seed clusters and the rest of the brain during an oddball salience processing task. Relative to the placebo condition, delta-9-THC and CBD had opposite effects on the functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Delta-9-THC reduced fronto-striatal connectivity, which was related to its effect on task performance, whereas this connection was enhanced by CBD. Conversely, mediotemporal-prefrontal connectivity was enhanced by delta-9-THC and reduced by CBD. Our results suggest that the functional integration of brain regions involved in salience processing is differentially modulated by single doses of delta-9-THC and CBD and that this relates to the processing of salient stimuli.

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Section: Introductionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

Bhattacharyya

Falkenberg

Martín‐Santos

et al. 2014

Neuropsychopharmacol

105

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“…23,32 This nding dovetails with the concept of proximal salience. 24 This concept proposes that the processing of incoming stimuli induces a proximal salience signal in the insula depending on its predictability, which indicates whether further downstream processing is required to adjust one's predictive model. The downstream processing includes motor action, updating the prefrontal fund of knowledge or stopping an activity that is ongoing.…”

Section: Discussionmentioning

confidence: 99%

“…1). These variations were guided by studies highlighting functional ACC-insula, 23,24 ACC-VS 25 and insula-VS 18,26 interactions during reward processing and by studies providing evi dence for an involvement of the visual cortex (and their connections to the insula and VS) in reward processing. 18,27 In particular, we allowed high-probability reward cues to modulate 1) only ACC-insula connectivity, 2) ACC-insula and ACC-VS connectivity, 3) ACC-insula, ACC-VS and insula-striatum connectivity, and 4) ACC-insula, ACC-VS, insula-striatum, visual cortex-insula and visual cortex-VS connectivity.…”

Section: Model Space Constructionmentioning

confidence: 99%

Dysfunctional insular connectivity during reward prediction in patients with first-episode psychosis

Schmidt

Palaniyappan

Smieskova

et al. 2016

jpn

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IntroductionOur brain is constantly exposed to a wide variety of stimuli, which compete for limited cognitive resources. External stimu li are processed depending on their salience so as to ignore predictable, state and task-irrelevant events while enhancing resource allocation in order to process unexpected or state-and task-relevant events. Efficient prediction of salient stimuli, such as those of rewards, is thus essential for adapting ongoing behaviour. This process requires the ability to learn that a neutral stimulus becomes emotionally endowed owing to its association with primary reinforcement. 1 Behavioural and fMRI studies have demonstrated impairments in patients with psychosis when anticipating reward.2 Relative to controls, behavioural evidence indicated that patients with rst-episode psychosis (FEP) exhibited less reactivity to reward-predicting cues.3 Functional MRI studies during reward prediction have reported reduced activity in diverse brain regions, including the ventral striatum (VS), 4,5 anterior cingulate cortex (ACC), midbrain, thalamus and cerebellum, of unmedicated patients with FEP compared with controls. 5 It has further been shown that VS activation during reward prediction was negatively related to positive psychotic symptoms in patients with FEP. 4,5 Reward processing is critically mediated by dopamine, 6,7 and the VS response to reward-predicting cues is likely triggered by dopamine activity. 8,9 A previous fMRI study in patients with chronic schizophrenia showed that the VS response during reward prediction was reduced only in patients treated with typical antipsychotics, whereas no difference was observed between healthy controls and patients treated with atypical medication. 10 In line with this nding in patients with chronic schizophrenia, the reduced baseline VS activation during reward prediction seen in patients with FEP relative to healthy controls has been reported to be normalized after 6 weeks of monotherapy with atypical antipsychotics.11 The largest improvement in positive symptoms was seen in patients with the highest VS signal increase.11 Although not speci cally during reward processing, a recent resting-state fMRI study in patients Background: Increasing evidence indicates that psychosis is associated with abnormal reward processing. Imaging studies in patients with first-episode psychosis (FEP) have revealed reduced activity in diverse brain regions, including the ventral striatum, insula and anterior cingulate cortex (ACC), during reward prediction. However, whether these reductions in local brain activity are due to altered connectivity has rarely been explored. Methods: We applied dynamic causal modelling and Bayesian model selection to fMRI data during the Salience Attribution Task to investigate whether patients with FEP showed abnormal modulation of connectivity between the ventral striatum, insula and ACC induced by rewarding cues and whether these changes were related to positive psychotic symptoms and atypical antipsychotic medication. Results: The model...

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“…The pACC is a key region for regulation of limbic activity 22 previously shown to be abnormal in schizophrenia 23 . Furthermore, the frontoinsular cortex is highly connected to the pACC, with which it forms the cortical aspects of the salience network 24 , a circuitry linked to schizophrenia risk 25 . Although reduction in the volume of the temporal lobe white matter is a well-established feature of schizophrenia and is present early in the illness 26 , the finding of increased callosal volume was unexpected, as patients with schizophrenia have reduced volume in this region 27 .…”

Section: Structural Mri Phenotypesmentioning

confidence: 99%

CNVs conferring risk of autism or schizophrenia affect cognition in controls

Stefánsson

Meyer‐Lindenberg

Steinberg

et al. 2013

Nature

626

568

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In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNVonly confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.Little information is available on whether or how rare CNVs conferring high risk of schizophrenia and/or autism affect physiologic function of otherwise normal brains. As none of these CNVs hitherto described are fully penetrant for the diseases, and both schizophrenia and autism affect cognition, we aimed to examine the possibility that the CNVs affect cognition in control carriers, those who do not suffer either disease or intellectual disability. We based our selection of CNVs on a literature search for CNVs associated with schizophrenia and/or autism ('neuropsychiatric CNVs'); this search produced 26 CNV alleles (Supplementary Table 1) 1-3 . These CNV alleles are rare, found in 0.002% to 0.2% frequency, and cumulatively in 1.16% of our sample of 101,655 genotyped subjects, representing approximately one-third of the Icelandic population ( Supplementary Tables 1 and 2).We used the subset of genotyped subjects born before 1968, without excluding patients, to examine the association of each neuropsychiatric CNV with reproductive outcome ('fecundity'), defined simply as the number of children each subject had by age 45. After correction for multiple comparisons, three neuropsychiatric CNVs were significantly associated with fecundity (Table 1). Subjects carrying the 16p11.2 deletion or the 22q11.21 duplication show reduced fecundity, with the effect in males significantly greater than in females (P 5 0.0083 and P 5 0.029 for the difference in effect by sex for the 16p11.2 deletion and the 22q11.21 duplication, respectively). In contrast, individuals carrying the 16p12.1 deletion have more children than do controls (Table 1). Those with deletions at 15q11.2(...

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Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction

Cited by 496 publications

References 152 publications

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

Dysfunctional insular connectivity during reward prediction in patients with first-episode psychosis

CNVs conferring risk of autism or schizophrenia affect cognition in controls

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