Schizophrenia is a complex neuropsychiatric disorder characterized by a wide range of neurocognitive, affective and neurodevelopmental abnormalities. Researchers have been trying to identify biomarkers or target features, known as endophenotypes, which encompass the genetic and non-genetic processes underpinning the predisposition to schizophrenia. However, the specificity of most of the identified biomarkers or endophenotypes for schizophrenia remains controversial. Neurological soft signs (NSS) have been considered promising endophenotypes for schizophrenia with the added advantage of being simple and user-friendly in clinical application.

Dr. CHAN Raymond’s team from the Institute of Psychology has demonstrated that NSS fulfill many criteria of an endophenotype for schizophrenia, including association with the illness, heritability, state-dependence, co-segregation, familial association, and being valid and reliable for measurement. Dr. CHAN’s team has also demonstrated in a small study the specificity of NSS in discriminating patients with schizophrenia from those with non-psychotic disorders. However, these studies were limited by small sample size and other confounding variables. A large-scale population-based study including clinical, sub-clinical, and healthy samples using a unified assessment of NSS and a rigorous matching procedure is needed. Moreover, little is known how NSS change over the human lifespan. The lack of any lifespan data hinders our understanding of the developmental trajectory of NSS in patients with schizophrenia. Lifespan information also allows us to integrate brain-behaviour phenotypes in a developmental context and identify critical age-related characteristics of the vulnerability to schizophrenia to provide valid tools for early detection.

To bridge the gap of this knowledge, Dr. CHAN and his international collaborators have conducted a large-scale study to specifically examine the clinical utility and the lifespan profiling of NSS in schizophrenia spectrum disorders. They administered the abridged version of the Cambridge Neurological Inventory to 1577 healthy individuals, 738 patients with schizophrenia, 155 first-degree relatives of schizophrenia patients, 256 individuals with schizotypy, and 379 patients with other neuropsychiatric disorders (e.g., major depressive disorder, bipolar disorder, obsessive-compulsive disorders). They adopted a rigorous statistical method to match and control for confounding variables. Their findings showed that individuals along the schizophrenia continuum exhibited elevated levels of NSS (moderate effect sizes) in contrast to patients with other neuropsychiatric disorders, who had minimal NSS, as well as matched healthy controls. More interestingly, when plotting the developmental trajectory of NSS against age, patients with schizophrenia showed a flat but overall elevated pattern, in contrast to a U-shaped pattern in healthy individuals.

Taken together, these findings suggest that NSS demonstrate good sensitivity in detecting neurodevelopmental abnormalities across the schizophrenia spectrum, i.e., schizophrenia > non-psychotic first-degree relatives > individuals with schizotypy >healthy controls. Moreover, NSS is also able to identify a moderate portion of the variance for psychosis proneness with reasonable specificity. Lifespan profiling reveals an abnormal developmental trajectory of NSS in schizophrenia patients, which supports the endophenotype hypothesis of NSS by associating it with the neurodevelopmental model of schizophrenia.

Dr. CHAN’s team and his collaborators are now taking further steps to combine the behavioural measures of NSS and trajectory-based neuroimaging measures to examine how variations in NSS manifest as structural and functional imaging abnormalities in patients with schizophrenia. They also aim to include genetic investigations in their study to link behavioural end ophenotypes with neurodevelopmental biomarkers to gain a better understanding of the pathogenesis of schizophrenia.

This study was supported by grants from the National Natural Science Fundation of China Outstanding Investigator Award, the Beijing Training Project for the Leading Talents in S & T, the National Basic Research Programme, and the CAS/SAFEA International Partnership Program for Creative Research Teams.

The paper is now available online from Schizophrenia Bulletin.