At the boundary of the self: The insular cortex in patients with childhood-onset schizophrenia, their healthy siblings, and normal volunteers

• We analyze longitudinal MRIs of patients with childhood-onset schizophrenia (COS).
• COS patients have significantly reduced total insula volume compared to volunteers.
• These deficits correlate with schizophrenia symptomology in patients with COS.
• Siblings of patients with COS did not differ from volunteers in insular volume.

The insular cortex (insula), whose normal function involves delineating the boundary between self and non-self stimuli, has been implicated in the pathophysiology of the positive symptoms of schizophrenia, including hallucinations and delusions. Childhood-onset schizophrenia (COS), that includes the onset of psychosis before age 13, is a severe and continuous form of the illness which shows profound and global progressive cortical brain abnormalities during adolescence which merge in the adult pattern with age. Using prospectively acquired anatomic brain magnetic resonance imaging (MRI) scans, a matched sample of COS patients, their nonpsychotic full siblings and healthy volunteers, we measured insular volume using the FreeSurfer automated software. COS patients (n = 98; 234 scans) had significantly lower right (p = 0.003), left (p < 0.001), and total (p < 0.001) insular volumes than healthy volunteers (n = 100; 248 scans). Right insular volume negatively correlated with positive symptoms as measured by the Scale for the Assessment of Positive Symptoms (SAPS) (p = 0.02), while both left (p = 0.01) and right (p = 0.006) insula volumes were positively correlated with overall functioning, as measured by the Children's Global Assessment Scale (CGAS) scores. COS siblings (n = 71; 153 scans), on the other hand, did not differ significantly from normal volunteers suggesting that the insular deficits are more related to the illness state than a familial endophenotype. These results also highlight the salience of the insula in positive symptoms of schizophrenia perhaps resulting from the inability to discriminate between self from the non-self in COS. Further work to connect insular deficits to other neurocircuitries is warranted.