Clinical Utility and Lifespan Profiling of Neurological Soft Signs in Schizophrenia Spectrum Disorders

Abstract

Neurological soft signs (NSSs) bear the promise for early detection of schizophrenia spectrum disorders. Nonetheless, the sensitivity and specificity of NSSs in the psychosis continuum remains a topic of controversy. It is also unknown how NSSs reveal neurodevelopmental abnormality in schizophrenia. We investigated the effect sizes of NSSs in differentiating individuals with schizophrenia spectrum disorders from individuals with other psychiatric conditions and from covariate-matched healthy subjects. We also investigated the partitioned age-related variations of NSSs in both schizophrenia and healthy individuals. NSSs were assessed by the abridged version of the Cambridge Neurological Inventory (CNI) in 3105 participants, consisting of healthy individuals (n=1577), unaffected first-degree relatives of schizophrenia patients (n= 155), individuals with schizotypal personality disorder (n= 256), schizophrenia patients (n= 738), and other psychiatric patients (n= 379). Exact matching and propensity score matching procedures were performed to control for covariates. Multiple regression was used to partition age-related variations. Individuals along the schizophrenia continuum showed elevated levels of NSSs, with moderate effect sizes, in contrast to other psychiatric patients who had minimal NSSs, as well as matched healthy controls. Furthermore, the age-and-NSS relationship in schizophrenia patients was represented by a flat but overall elevated pattern, in contrast to a U-shaped pattern in healthy individuals. In sum, NSSs capture a moderate portion of psychosis proneness with reasonable specificity. Lifespan profiling reveals an abnormal developmental trajectory of NSSs in schizophrenia patients, which supports the endophenotype hypothesis of NSSs by associating it with the neurodevelopmental model of schizophrenia.

Keywords: endophenotype; lifespan profiling; neurological soft sign; psychopathology; schizophrenia spectrum disorders.

Fig. 1.

Effect sizes (r) of group differences in NSSs in terms of nonhealthy vs healthy group comparisons before (a) and after exact matching (b) and propensity score matching (c). Greater value of r means that the nonhealthy comparison group shows more NSSs compared to the healthy group. Error bars denote 95% confidence intervals (CIs). NSS, neurological soft sign; OP, other psychiatric; Schi., schizophrenia; SPD, schizotypal personality disorders.

Fig. 2.

Age-and-NSS associations in healthy and schizophrenia samples. (a) The overall relationship between age and NSSs in healthy and schizophrenia samples (n = 2315); (b) The relationship between age and NSSs in the healthy group (n = 1577); (c) the relationship between age and NSSs in the healthy group after matching the age range with the schizophrenia group (n = 1224); (d) the relationship between age and NSSs in schizophrenia group (n = 738). The transparent black dots are actual data points, with the less opacity representing more data points on certain values. The black solid lines represent the negative binomial regression predictions of the quadratic age effect on NSSs, and the surrounding broken red lines indicate 95% confidence intervals (CIs) of the estimations. NSS, neurological soft sign; OP, other psychiatric; SPD, schizotypal personality disorders.