Negative symptoms, a major contributing factor to poor functional outcomes in patients with schizophrenia, are often more persistent than positive symptoms. The construct of Persistent Negative Symptoms (PNS) has been put forward to describe negative symptoms that are enduring, trait-like features of psychotic disorders that are resistant to currently available treatment. The presence of PNS affects a large number of clinical patients with schizophrenia. However, the current diagnostic criteria for PNS are not based on the latest re-conceptualization of negative symptom assessment such as the Clinical Assessment Interview for Negative Symptoms (CAWS). Deriving PNS proxy from such a new rating scale is critically important for clinical trials and the use of these new measures to identi勿more clinically homogeneous subgroups.
Moreover, it is still not fully clear for the altered brain structural and functional connectivity associated with patients with PNS. The present study aimed to address these issues with the use of the newly developed and validated CAINS in patients with PNS and to examine the associated altered brain structural and functional connectivity observed in these patients. In Study 1，a total of 206 patients with schizophrenia were recruited and divided into the PNS group (n=57) and the Non-PNS group (n=149) using the conventional PNS criteria developed using the SANS. To determine which PNS cut-offs should be established with the CAWS, Receiver Operating Characteristic (ROC) curve analysis was evaluated for the CAWS subscales and total scores in the PNS and Non-PNS groups. The findings showed that PNS cutoffs of CAWS total scores, Motivation and Pleasure (MAP) subscale score and Expression (EXP) subscale score were 25, 17, and 5, respectively. Area Under the Curve (AUC) indicated excellent discrimination of the PNS and Non-PNS groups using the cut-score for the total scale. The discrimination for MAP was better than EXP. The Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of the MAP subscale were 81.54% and 97.16%. These findings suggest that the PNS cut-scores derived for the CAWS are comparable to existing scales. The proxy tool offers a novel means of identifying PNS patients in clinical trials using a next-generation scale that overcomes methodological and conceptual limitations of older scales.
In Study 2, we firstly conducted an Activation Likelihood Estimation (ALE) meta-analysis to quantitatively examine brain grey matter reduction in schizophrenia patients with PNS. A total of 12 voxel-based morphometry (VBM) studies were included in ALE meta-analysis using more stringent criterion of PNS. Significant grey matter reduction in the PNS group relative to controls was observed in the left caudate nucleus, the left precentral region, the left middle frontal region, the bilateral parahippocampal region, the left anterior cingulate region, the bilateral medial frontal gyrus, the thalamus and the insula. In the second part of Study 2, we recruited 26 patients with PNS, 31 with non-PNS, and 33 healthy controls to undertake the MRI scans and T1 imaging. VBM analysis showed that there was no significant grey matter reduction found between PNS group and non-PNS group. However, comparing to healthy controls, PNS group showed much more grey matter reduction, especially at the prefrontal regions. We also found that the grey matter reduction in the left cingular gyrus were associated with the severity of negative symptoms in both groups of patients with PNS and non-PNS. Taken together, these findings suggested that the grey matter reduction of PNS were mainly located in the prefrontal cortex and subcortical regions, such as the parahippocampal gyrus, thalamus and cingulate gyrus……