BACKGROUND: Schizophrenia is a serious brain illness that indicates many abnormalities in the functions of the brain’s fiber connections such as assessing the reality, thought, emotion and cognition. These fibers effect cognitional functions by connecting cortical and subcortical areas and networks formed by them. Aberrant brain connectivity especially in the prefrontal and temporal heteromodal cortex has been suggested as the essential mechanism underlying the disease. In this study, it is intended to investigate the post- and pre-treatment changes with diffusion tensor imaging MRI (DTI-MRI) in the splenium and genu regions of the corpus callosum in patients diagnosed with first-episode schizophrenia according to the DSM-IV-TR.
METHOD: Between June 2009 and February 2010, 18 patients with psychotic symptoms were recruited from the outpatient unit of the GMMA Haydarpasha Research and Training Hospital. These patients had been diagnosed with first-episode schizophrenia (n=7) or schizophreniform disorder (n=11) and matched inclusion criteria. Patients with schizophreniform disorder as initial diagnosis were reevaluated after 6 months, and this time schizophrenia diagnosis was a ascertained. By means of implementation of SCID-II, additional diagnoses for personality disorder were excluded. Two of the 18 patients who had been admitted to the study were excluded because of being diagnosed with short-term psychotic disorder, and two patients were unable to proceed because of incompatibilitywith MRI device. Three participants with schizophrenia were excluded from this study because of unsatisfactory image data due to head and body movement in the follow-up MRI scan. DTI-MRI was obtained from participants at baseline and after 4 weeks of standard antipsychotic treatment follow-up. A ‘difference color-coded fractional anisotropy (FA) map’ for each of the 11 patients was calculated from the 4-week follow-up and the baseline splenium and genu FA ROI (Region of Interest)-based measurements. Finally, this study included participants of whom 14 had completed baseline, 11 both baseline and follow-up experiment and 16 control persons who had no organic or psychiatric disease and whose age, sex and education level was matched with the patient group. Patients included in the study were hospitalized, all tests and measurements were implemented before starting on antipsychotics, then standard antipsychotic treatments (Risperidone (n=12), Paliperidone (n=2)) were continued. Patients’ family histories were received and they were examined mentally, physically and neurologically. Initially liver, kidney and thyroid functions of all patients were examined. In addition, structural brain abnormalities were evaluated during the
DTI measurements. To be eligible, criteria of involvement for either patients or healthy control subjects were: between 18 and 45 years old, being righthanded, first application to psychiatry, at least primary school graduate, no abuse of nicotine or caffeine, no DSM-IV-TR Axis I and Axis II comorbidity, a written consent (for patients by first-degree relatives). Criteria for being excluded: clinically conspicuous medical or neurological illness, having received antipsychotic treatment at the time of application or before or having used benzodiazepine longer than two weeks, for necessity of ECT (Electroconvulsive therapy), an incompatibility with MRI device and communication because of language problems and illnesses. The study was started after submitting the study protocol to the Istanbul Clinical Research Ethics Board and receiving approval from there (Number of decision: 2009-CC-040/11.12.2009) DTI
Image Analysis: FA maps were calculated with Siemens® syngo VE27A SL0109 Syngo Multimodality Workplace AG 2007 according to Basser et al. Major eigenvector linear maps were transformed into color codes. In the second stage, in advance of measurements 3D correction (Eddy Current Correction) was implemented to remove artifacts of emerging images. ROI radiuses were determined as 2 mm in the genu, 3 mm in the splenium. Hereby FA values were calculated accurately.
Statistic Evaluation: Acquired parameters from the study were evaluated with Statistical package for Social Sciences for Windows 16.0 (SPSS 16.0). Study parameters were expressed with average±standard deviation and percentage values. Group differences were assessed at baseline using independent group Student’s t-tests or χ²-tests, whereas longitudinal changes between the baseline and follow-up time points in the patients’ group was examined using paired Student’s t-tests. Significance level was based on p0.05). First-episode schizophrenia group’s economic level was lower than in healthy controls (χ²=5.275, p=0.022). DUP was identified as 2.3±1.7 months. Family history for schizophrenia was identified as 28.6%. In the first-episode schizophrenia group, an FA value of the genu region of the corpus callosum was determined as 0.690±0.124 and 0.834±0.042 for the control group. The FA value for the Splenium region was determined as 0.764±0.112 for the first-episode schizophrenia group and 0.852±0.031 for the control group. In the first-episode schizophrenia group, FA values detected both in the genu (t15.6=4.1, p<0.001) and the splenium (t14.8=2.8, p<0.01) were lower than in the control group. Follow-up measurements in the genu and splenium region of the corpus callosum determined FA values of respectively 0.711±0.133 and 0.790±0.056 for the FES group. There were mild fractional anisotropy increases respectively in genu and splenium (t10=-0.646, p=0.533; t10=-1.051, p=0.318) among FES patients following treatment. A negative correlation (Pearson’s r=-0.569, p=0.034) was detected between baseline splenium FA values and BPRS scores. The duration of illness prior to treatment was negatively correlated (r=0.066, p=0.846) between baseline and follow-up splenium FA changes. There were no significant correlations between the change in genu and splenium FA value and the improvement in clinical symptoms, PANSS total (r=-0.310, p=0.354, r=-0.583, p=0.060) and BPRS score (r=-0.087, p=0.800, r=-0.137, p=0.689) after 4 weeks of treatment. Moreover, there were no significant correlations between the change in genu and splenium FA value and the dose of antipsychotic medications (r=0.359, p=0.279; r=0.299, p=0.372).
DISCUSSION: In our DTI study, a reduction in FA values in the genu and splenium regions of the corpus callosum and a more apparent decrease in the genu were determined in first-episode drug-naive schizophrenia patients. Also, a negative correlation was determined between BPRS scores and baseline splenium FA values. Although the callosal FA changes did not correlate with symptom improvement or the dose of antipsychotic medication statistically, there was a mild increase in follow-up FA measurements. Four weeks might be too short to observe changes in white matter integrity. However, a potential toxic effect of antipsychotic medication, including oxidative stress and excitatory neurotoxicity, might be responsible for insufficient follow-up FA changes. On the other hand, the existence of white matter changes even in first-episode drug-naive schizophrenia patients supports the view that these problems occurs in stages of development, because the degree of FA changes refers to the fiber tract organization’s degree of function1 . They have a positive correlation. Moreover, the reduction of FA values directly indicates histological abnormalities. Also, our findings overlap significantly with those described by Wang et al.2 who reported that there was a significant decrease in absolute FA in the white matter in 35 first-episode drug-naive patients with schizophrenia and after 6 weeks of antipsychotic treatment that did not correlate with symptom reduction. As a result of white matter studies, distensions were detected in schizophrenia patients, particularly in axonal atrophy and periaxonal oligodendrocyte in the prefrontal cortex. This was deemed compatible with increased radial permeability and decreased FA values in the white matter of schizophrenia patients. This also suggests a cause from changes in axons’ skeletal structure or demyelinization rather than a big degeneration in axons3 . These findings show that the CC, which is the main determiner of interhemispheric connection, is affected distinctly in schizophrenia patients. When all these findings are considered, all of them probably result in a neuro-developmental defect that creates a shortage in neurons’ modulator capacity paving the way to changes in cellular morphology; then abnormal synaptic circuits come into existence. Consequently, we report FA reductions especially in the posterior region, also insufficient FA increase in white matter after antipsychotic treatment in patients experiencing a first episode of psychosis. However, prospective collaborative studies are needed to clarify the potential long-term effects of antipsychotics on white matter microstructure and also its reversibility.