The present study sought to investigate anterior insula GMV changes in a heterogeneous sample of young psychiatric patients, and if such GMV changes related to severity of clinical symptoms or impairments in neurocognitive executive functioning. This study revealed that compared to age-matched healthy participants, young psychiatric patients have reduced left anterior insula GMV that positively correlated with neurocognitive performance in an attentional set-shifting task. GMV loss or gain in the right anterior insula was associated with increased general psychiatric symptom severity (BPRS Total score) and increased positive symptoms (BPRS Positive Symptoms subscore).
The major finding from this study is that young people with emerging mental disorders have reduced left anterior insula GMV that correlates with worse executive functioning (Tables 2
5), in particular, set-shifting. The asymmetry of a larger left insula relative to the right insula is most apparent in humans, with less hemispheric difference seen in similar-sized lower primates , and this feature is hypothesised to be due to the left insula’s role in human language and language-associated functions . This present study’s findings that left anterior insula GMV is positively correlated with attentional set-shifting (IED) but not verbal fluency (COWAT), working memory (SSP) or sustained attention (RPV-A) suggests that the left anterior insula may be more closely involved in attentional processing rather than vocabulary memorisation. Interestingly, attention is conspicuously affected in all psychiatric disorders , and hence anterior insula degradation may be a core biological marker in this neurocognitive deficit. This result reinforces the “salience network” hypothesis [22, 25] that the anterior insula is involved in modulating reactivity to salient internal and extrapersonal stimuli, and this attentional executive function is impaired in young psychiatric patients with a broad variety of disorders.
The modulation of altered afferent interoceptive input, self-referential and belief-based states, and poorly predictive signals has been proposed as a neuroanatomical model for depression and anxiety . One model of anxiety suggests that neurons in the anterior insula estimate an “interoceptive prediction error” which signals a mismatch between anticipated and actual bodily responses to a potentially aversive stimulus . Studies demonstrating increased insula activation during emotion processing in depressive and anxiety-prone individuals [91, 93] strengthens the argument that degradation of the anterior insula might result in maladaptive motivating signal for individuals to withdraw (depression) or avoid (anxiety) situations. This study found there was no significant relationship between clinical measures of general anxiety (DASS) or depression (HDRS, DASS, BPRS depression subscore) and changes in anterior insula GMV (Tables 3 and 4), highlighting that anterior insula degradation in depression and anxiety may be a functional dysregulation rather than a structural alteration.
Both increases and decreases in right anterior insula GMV were associated with more positive symptoms (Table 4), namely hostility, grandiosity, suspiciousness, hallucinations, unusual thought content, bizarre behaviour, and conceptual disorganization. It has been suggested that since the insular cortex provides connections between the limbic memory regions and sensory systems, altered insula function may result in unbalanced sensory-memory integration, such as sensory hallucinations . Indeed, an fMRI study  of psychotic patients found auditory hallucinations co-occurred with significant hyperactivity within the right anterior insula and to a lesser extent the left insula. One structural MRI paper investigating GMV changes in schizophrenia  found that schizophrenic patients with hallucinations had reduced bilateral insula GMVs when compared to healthy controls, and reduced left insula GMVs when compared to schizophrenic patients without hallucinations. This present study demonstrates that in younger patients, positive symptoms are related with any imbalance of the right anterior insula GMV, consistent with the hypothesis of a hemispheric imbalance of salience switching [22, 25] which may underlie dysfunctional sensory awareness and interpretation .
Changes in right anterior insula GMV were associated with increased clinical symptom severity as measured by the BPRS Total score (Table 4). Other clinical scales employed in this study specifically targeting depression (DASS, HDRS), anxiety (DASS), psychological stress (K-10, DASS) and social functioning (SOFAS) were not correlated with anterior insula GMV changes. Considering that the BPRS Total score encompasses a depression subscore, the significant result of the BPRS Total score is probably due to the positive symptom subscore result discussed above. However, since the BPRS Total score is the summation of 24 questions it might be considered to be the largest, most robust measure of symptom severity in this study. Accordingly, the BPRS Total score may be a robust measure of symptom severity in young people arising from changes in right anterior insula GMV.
The relationship between anterior insula GMV and clinical measures of social anxiety remains inconclusive (Tables 3
4). The SIAS self-report assesses fears of social interaction situations and has been demonstrated to discriminate people diagnosed with social anxiety disorder from healthy controls  and other anxiety disorders . In this study the SIAS score had a weak but significant positive linear correlation with the right anterior insula GMV (Table 3), suggesting that reductions in anterior insula GMV equate to reductions in social anxiety and vice-versa. Future research could further investigate associations between anterior insula GMV changes and social anxiety severity using a larger cohort of patients in combination with other anxiety scales such as the clinician-administered Liebowitz Social Anxiety Scale [LSAS; ], the consumer-supported Social Phobia and Anxiety Inventory [SPAI; [100, 101]], or the refined self-report SIAS  with the companion Social Phobia Scale [SPS; ].
The influence of medication on changes in GMV remains contentious. Antidepressants, antipsychotics and mood stabilisers can be neuroprotective in patients and animal models of psychiatric disorders [reviewed in ]. A recent meta-analysis  suggest that antipsychotic medication may contribute to some structural changes noted in psychosis patients, though the authors concede that this may be confounded by disease progression . A ROI MRI study of psychosis patients  found that insula gray matter volume was not influenced by antipsychotic medication, and a follow-up study with bipolar patients  found that insula volume was not affected by lithium or valproate medication. In the young patients examined in this study, there was no evidence suggesting a relationship between antidepressants, antipsychotics or mood stabilisers with anterior insula GMV changes. Future research could examine how anterior insula GMV may be affected by specific medications, as well as the impact of medication switching over time.
Future studies can enhance the findings of this present cross-sectional study. A longitudinal protocol is needed to investigate the relationship between anterior insula GMV, clinical symptoms and neuropsychological performance over time. Furthermore, such relationships should be contrasted along a trajectory of clinical course and functional impairment as proposed by McGorry, Hickie et al [49, 50]. The insular cortex has also been implicated in addictive behaviour  and the relationship between anterior insula GMV and drug and alcohol use requires further investigation. Finally, whilst this present study found that a group of affective/psychosis patient exhibited reduced anterior insula GMV (Table 2), increases in anterior insula GMV correlating with increased symptom severity (Table 4) may apply to patients with autism spectrum disorder which have been shown to have enlarged insula GMVs relative to healthy controls .