Lena Palaniyappan

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

The insular cortex is one of the brain regions that show consistent abnormalities in both structural and functional neuroimaging studies of schizophrenia. In healthy individuals, the insula has been implicated in a myriad of physiologic functions. The anterior cingulate cortex (ACC) and insula together constitute the salience network, an intrinsic large-scale network showing strong functional connectivity. Considering the insula as a functional unit along with the ACC provides an integrated understanding of the role of the insula in information processing. In this review, we bring together evidence from imaging studies to understand the role of the salience network in schizophrenia and propose a model of insular dysfunction in psychosis.

Neural Primacy of the Salience Processing System in Schizophrenia

Summary For effective information processing, two large-scale distributed neural networks appear to be critical: a multimodal executive system anchored on the dorsolateral prefrontal cortex (DLPFC) and a salience system anchored on the anterior insula. Aberrant interaction among distributed networks is a feature of psychiatric disorders such as schizophrenia. We used whole-brain Granger causal modeling using resting fMRI and observed a significant failure of both the feedforward and reciprocal influence between the insula and the DLPFC in schizophrenia. Further, a significant failure of directed influence from bilateral visual cortices to the insula was also seen in patients. These findings provide compelling evidence for a breakdown of the salience-execution loop in the clinical expression of psychosis. In addition, this offers a parsimonious explanation for the often-observed “frontal inefficiency,” the failure to recruit prefrontal system when salient or novel information becomes available in patients with schizophrenia.

Brain Surface Anatomy in Adults With Autism: The Relationship Between Surface Area, Cortical Thickness, and Autistic Symptoms

CONTEXT Neuroimaging studies of brain anatomy in autism spectrum disorder (ASD) have mostly been based on measures of cortical volume (CV). However, CV is a product of 2 distinct parameters, cortical thickness (CT) and surface area (SA), that in turn have distinct genetic and developmental origins. OBJECTIVE To investigate regional differences in CV, SA, and CT as well as their relationship in a large and well-characterized sample of men with ASD and matched controls. DESIGN Multicenter case-control design using quantitative magnetic resonance imaging. SETTING Medical Research Council UK Autism Imaging Multicentre Study. PARTICIPANTS A total of 168 men, 84 diagnosed as having ASD and 84 controls who did not differ significantly in mean (SD) age (26 [7] years vs 28 [6] years, respectively) or full-scale IQ (110 [14] vs 114 [12], respectively). MAIN OUTCOME MEASURES Between-group differences in CV, SA, and CT investigated using a spatially unbiased vertex-based approach; the degree of spatial overlap between the differences in CT and SA; and their relative contribution to differences in regional CV. RESULTS Individuals with ASD differed from controls in all 3 parameters. These mainly consisted of significantly increased CT within frontal lobe regions and reduced SA in the orbitofrontal cortex and posterior cingulum. These differences in CT and SA were paralleled by commensurate differences in CV. The spatially distributed patterns for CT and SA were largely nonoverlapping and shared only about 3% of all significantly different locations on the cerebral surface. CONCLUSIONS Individuals with ASD have significant differences in CV, but these may be underpinned by (separable) variations in its 2 components, CT and SA. This is of importance because both measures result from distinct developmental pathways that are likely modulated by different neurobiological mechanisms. This finding may provide novel targets for future studies into the etiology of the condition and a new way to fractionate the disorder.

Structural correlates of auditory hallucinations in schizophrenia: a meta-analysis.

BACKGROUND Despite being one of the most common symptoms of schizophrenia, determining the neural correlates of auditory hallucinations still remains elusive with various studies providing inconsistent results. METHODS We conducted a voxel-based meta-analysis of studies investigating the structural correlates of auditory hallucinations in schizophrenia. RESULTS 7 datasets including 350 patients were identified. There was a significant negative correlation between the severity of hallucinations and gray matter volume in the left insula and right superior temporal gyrus. CONCLUSION With its key role in stimulus evaluation and optimizing prediction (proximal salience), the insula is likely to be a cardinal region along with superior temporal gyrus in the mechanism of auditory hallucinations in schizophrenia.

Differential effects of surface area, gyrification and cortical thickness on voxel based morphometric deficits in schizophrenia.

Voxel Based Morphometry (VBM) and Surface Based Morphometry (SBM) are the two most commonly used methods to study the structure of gray matter in various disease states such as schizophrenia. Though overlapping changes have been observed in same datasets using the two procedures, the proportional contribution of the anatomical properties of the cortical mantle such as thickness, surface area and gyrification to the group differences in gray matter volume (GMV) observed using VBM is unknown. In the present study, we investigate the relationship between the GMV and the anatomical properties of the cortical mantle in regions showing significant VBM changes in schizophrenia using a sample of 57 patients and 41 healthy controls. To this end, we obtained significant clusters showing VBM changes in schizophrenia and studied the contribution of the three anatomical properties derived from SBM to the observed group differences in the GMV using a multiple mediation analysis. Our results suggest that while SBM measures make distinct but regionally variable contribution to the VBM differences, a large proportion of the group difference observed using VBM is not explained by the individual surface anatomical properties. While VBM may be more sensitive in identifying the regions with gray matter abnormalities, studies investigating the pathophysiology of illnesses such as schizophrenia are better informed when both SBM and VBM analyses are performed concurrently.

Aberrant cortical gyrification in schizophrenia: a surface-based morphometry study.

BACKGROUND Schizophrenia is considered to be a disorder of cerebral connectivity associated with disturbances of cortical development. Disturbances in connectivity at an early period of cortical maturation can result in widespread defects in gyrification. Investigating the anatomic distribution of gyrification defects can provide important information about neurodevelopment in patients with schizophrenia. METHODS We undertook an automated surface-based morphometric assessment of gyrification on 3-dimensionally reconstructed cortical surfaces across multiple vertices that cover the entire cortex. We used a sample from our previous research of 57 patients (50 men) with schizophrenia and 41 controls (39 men) in whom we had tested a specific hypothesis regarding presence of both hypo and hypergyria in the prefrontal cortex using a frontal region-of-interest approach. RESULTS Regions with significant reductions in gyrification (hypogyria) were seen predominantly in the left hemisphere, involving the insula and several regions of the multimodal association cortex. Although the prefrontal hypergyria documented earlier did not survive the statistical correction required for a whole brain search (cluster inclusion at p = 0.0001), significant hypergyric frontal clusters emerged when the threshold was lowered (cluster inclusion at p = 0.05). In the insula, a reduction in gyrification was related to reduced cortical thickness in patients with schizophrenia. LIMITATIONS We studied a sample of patients taking antipsychotic medications, which could have confounded the results. Our sample was predominantly male, limiting the generalizability of our findings. CONCLUSION Our observations suggest that the disturbances in cortical gyrification seen in patients with schizophrenia might be related to a disrupted interaction between the paralimbic and the multimodal association cortex and thus might contribute to the pathogenesis of the illness.

Folding of the Prefrontal Cortex in Schizophrenia: Regional Differences in Gyrification

BACKGROUND Anatomy of prefrontal cortex in schizophrenia has been studied previously by quantifying the degree of gyrification. Conflicting results exist, with some studies showing hypergyria and others showing hypogyria. It is likely that regional variations in cortical folding exist within the prefrontal cortex that could be explored by studying the anatomical subdivisions formed by the sulci and gyri. With surface reconstructions from magnetic resonance imaging, we studied the gyrification within anatomically meaningful subdivisions of prefrontal cortex in schizophrenia. METHODS Prefrontal cortex was studied with an automated method to obtain Local Gyrification Index, reflecting the degree of cortical folding in 57 patients with schizophrenia and 42 control subjects. Regional differences within prefrontal cortex were compared between the two groups with a sulcogyral atlas. Effects of hemisphere and age were subsequently assessed. RESULTS Patients with schizophrenia had significant hypogyria in most prefrontal regions except the frontomarginal region, which showed hypergyria. The normal left > right pattern of prefrontal gyrification was reversed in schizophrenia. Patients with schizophrenia also showed significant age-related reduction in gyrification at the hypogyric regions. CONCLUSIONS The differences between reported findings regarding prefrontal gyrification might reflect regional variation in the nature of the abnormal process of gyrification in schizophrenia. Prefrontal gyrification is significantly influenced by age in schizophrenia, in addition to the influence of neurodevelopmental factors.

Reality distortion is related to the structure of the salience network in schizophrenia

BACKGROUND An intrinsic cerebral network comprising the anterior cingulate and anterior insula (the salience network) is considered to play an important role in salience detection in healthy volunteers. Aberrant salience has been proposed as an important mechanism in the production of psychotic symptoms such as delusions and hallucinations (reality distortion). We investigated whether structural deficits in the salience network are associated with the reality distortion seen in schizophrenia. METHOD A sample of 57 patients in a clinically stable state of schizophrenia and 41 controls were studied with high-resolution magnetic resonance imaging. RESULTS Bilateral volume reduction was seen in the anterior cingulate and anterior insula in patients with schizophrenia. Reduced volume in the two left-sided regions of the salience network was significantly correlated with the severity of reality distortion. CONCLUSIONS These findings suggest that a deficit of grey matter in the salience network leads to an impaired attribution of salience to stimuli that is associated with delusions and hallucinations in schizophrenia.

Localized connectivity in depression: A meta-analysis of resting state functional imaging studies

Resting-state fMRI studies investigating the pathophysiology of depression have identified prominent abnormalities in large-scale brain networks. However, it is unclear if localized dysfunction of specialized brain regions contribute to network-level abnormalities. We employed a meta-analytical procedure and reviewed studies conducted in China investigating changes in regional homogeneity (ReHo), a measure of localized intraregional connectivity, from resting-state fMRI in depression. Exploiting the statistical power gained from pooled analysis, we also investigated the effects of age, gender, illness duration and treatment on ReHo. The medial prefrontal cortex (MPFC) showed the most robust and reliable increase in ReHo in depression, with greater abnormality in medication-free patients with multiple episodes. Brain networks that relate to this region have been identified previously to show aberrant connectivity in depression, and we propose that the localized neuronal inefficiency of MPFC exists alongside wider network level disruptions involving this region.

Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: a systematic review and meta-analysis

Electroconvulsive therapy (ECT) is the most effective treatment of depression. During the last decades repetitive transcranial magnetic stimulation (rTMS), an alternative method using electric stimulation of the brain, has revealed possible alternative to ECT in the treatment of depression. There are some clinical trials comparing their efficacies and safeties but without clear conclusions, mainly due to their small sample sizes. In the present study, a meta-analysis had been carried out to gain statistical power. Outcomes were response, remission, acceptability and cognitive effects in depression. Following a comprehensive literature search that included both English and Chinese language databases, we identified all randomized controlled trials that directly compared rTMS and ECT for major depression. 10 articles (9 trials) with a total of 425 patients were identified. Methodological quality, heterogeneity, sensitivity and publication bias were systematically evaluated. ECT was superior to high frequency rTMS in terms of response (64.4% vs. 48.7%, RR = 1.41, p = 0.03), remission (52.9% vs. 33.6%, RR = 1.38, p = 0.006) while discontinuation was not significantly different between the two treatments (8.3% vs. 9.4%, RR = 1.11, p = 0.80). According to the subgroup analysis, the superiority of ECT was more apparent in those with psychotic depression, while high frequency rTMS was as effective as ECT in those with non-psychotic depression. The same results were obtained in the comparison of ECT with low frequency rTMS. ECT had a non-significant advantage over high frequency rTMS on the overall improvement in HAMD scores (p = 0.11). There was insufficient data on medium or long term efficacy. Both rTMS and ECT were well tolerated with only minor side effects reported. Results based on 3 studies suggested that specific cognitive domains such as visual memory and verbal fluency were more impaired in patients receiving ECT. In conclusion, ECT seemed more effective than and at least as acceptable as rTMS in the short term, especially in the presence of psychotic depression. This review identified the lack of good quality trials comparing the long-term outcome and cognitive effects of rTMS and ECT, especially using approaches to optimize stimulus delivery and reduce clinical heterogeneity.