Schizophrenia is a chronic disabling mental illness and has been listed as a major public health issue comparable to that of the HIV epidemic (1). The incidence of schizophrenia is ~1% worldwide (2). Its cause, however, remains unclear. There have been advances in the treatment options to control symptoms but the prognosis for the majority of patients remains poor with the majority of patients staying incapacitated for life (3). New evidence seems to indicate that white matter abnormalities may be an important pathophysiological finding in schizophrenia (4); however, the results are inconsistent. Previous findings have shown that the seriousness of negative symptoms of schizophrenia may be associated with more intense white matter abnormalities (5), although other authors have found opposing results (6) complicating the analysis. The focus thus far has been on initial positive symptoms, therapeutic effects in patients with negative symptoms, social function and the extent of damage and prognosis, where there is a tendency to identify brain cell loss and degeneration (7).

Diffusion-tensor tractography (DTT) is a new magnetic resonance imaging (MRI) technology characterized by being non-invasive, not requiring exogenous contrast agents (8). It measures dispersion characteristics throughout nervous tissues, and is the only method providing high-quality biological tissue imaging to obtain clinical information, physical properties, microstructure and structural up-to-date data. Diffusion-tensor imaging (DTI) can identify abnormalities in the brain white matter microstructure, and is widely used in studies of brain connection structures in schizophrenia (9). Compared with single techniques, the combined applications of the region of interest (ROI), such as brain analysis based on voxel (VBA) and fiber tracking (FT) in DTI, as well as data statistical analysis methods have a higher diagnostic accuracy, and can produce real and reliable results (10). Different MRI analysis methods and FT have been combined and applied to children with retinal congenital malformations, congenital brain malformation, amyotrophic lateral sclerosis, computing capacity in developmental disorders as well as to healthy individuals, achieving promising results (11). However, to the best of our knowledge, this is the first study to be applied to schizophrenic patients.

A previous meta-analysis concluded that the white matter abnormalities of schizophrenia are mainly located on the left prefrontal deep and deep white matter in the left temporal lobe (12). However, findings of other studies have shown that schizophrenia with typical first negative symptoms is correlated with complete damage in the inferior frontal gyrus white matter (13). The present study used VBA and FT on structural integrity of white matter in schizophrenic patients with typical first negative symptoms to obtain more accurate results.

Positive and negative symptoms are independent of each other (15). A negative symptom is a reduction or loss of the normal function, consisting of a defective function, such as poor thought, bleak emotion, depression and passive social withdrawal. Negative symptoms can become stable over time and are associated with poor cognitive development, poor premorbid state, drug resistance and poor prognosis in the chronic phases (16). A type of schizophrenia with predominantly negative symptoms is classified as a special group of the disease. The analysis of the type of brain connections in cases presenting negative symptoms can reduce the heterogeneity effect of the sample on the study results, and can be useful in elucidating clearly the function of the abnormal brain connections in the pathogenesis of schizophrenia (16). Assuming that FA can reflect the nerve fiber connectivity of the white matter in the brain, the reduction of FA represents damage of regional cerebral white matter integrity and the reduction of nerve fiber connectivity. Previous findings have shown that the patients with schizophrenia mainly have structural abnormalities of the middle frontal lobe (complex of hippocampus-amygdala and entorhinal cortex), the superior frontal gyrus, the hippocampal sulcus, the corpus callosum, the frontal lobe and the cingulate gyrus (17).

DTI can demonstrate the shape of white matter tracts, allowing for observation of the structural characteristic of the brain's white matter, and revealing microchanges in the brain white matter nerve fiber tracts of schizophrenics, providing evidence for a possible neuropathological basis. FA is an important expression parameter of DTI, as it refers to the proportion of anisotropic water molecules in the whole diffusion tensor, and is able to reflect the diffusion anisotropy of water molecules and reveal the ordering of the tissue microstructures (18). Its size is correlated with the integrity of the myelin sheath, fiber compactness, and parallelism. Compared with relative anisotropic values and volume ratio values, FA values are characterized by less variability and higher imaging signal to noise ratio (19). DTT is the only non-invasive imaging method to display brain white matter fiber tracts on the living body; however, it lacks a golden standard to test its reliability. Tractography is divided into two methods: One involves line propagation techniques, and the other energy minimization techniques. The present study utilized the former technique, where seed and tracking conditions for the termination of the fiber bundle were established, and computers automatically displayed marked 3D fiber bundles, as previously described by Chung et al (20). The reliability of DTT results are influenced by image acquisition quality, applied algorithms, control parameters, ROI location and proficiency of relevant anatomical knowledge by the operator (21).

Among the brain structures identified as defective in the study, the corpus callosum is the largest commissural fiber that bears the function of information transfer and integration between the two cerebral hemispheres, including organizing hand movement and unifying emotion. Furthermore, it is associated with memory retrieval function, attention and wake-up states, and speech and hearing functions. It is an integral part of the active state of a person (22). It is generally considered that the left hemisphere of the brain is responsible for abstract thinking while the right one is responsible for imagery thinking (23). However, only by integrating abstract and imagery thinking constantly by means of connections can a person maintain a normal mode of thinking. When this connection is insufficient, abstract thinking and imagery thinking become fragmented, and thus abnormal thinking may occur (24).

In conclusion, the reduction of the FA values in the left deep prefrontal cortex, right deep temporal lobe, white matter of the inferior frontal gyrus and part of the corpus callosum may be associated with the pathogenesis of schizophrenia with typical first negative symptoms. Thus, the application of MRI DTI-FT is potentially valuable in improving diagnostic accuracy.