CORRELATION ANALYSIS BETWEEN THE MORPHOMETRIC CHARACTERISTICS OF THE HEAD OF NUCLEUS CAUDATUS AND THE INTENSITY OF PSYCHOTIC MANIFESTATION IN SCHIZOPHRENIA

Introduction: One of the significant functional disorders of the central nervous system in patients with schizophrenia is the increased activity of the mesolimbic dopaminergic system. By the nigrostriatal pathway, the caudate nucleus is closely related to other dopaminergic systems of the brain. Since the function of caudate nucleus relies on the action of dopamine in the brain; the role of this anatomical structure in the pathogenesis of schizophrenia is not sufficiently clarified. The aim of this paper was to examine whether the caudate nucleus participates in the modulation of the intensity of psychotic manifestations in schizophrenia. Patients and Methods: The study included a total of thirty-one patients with schizophrenia. Diagnosis of the schizophrenia was based on the DSM-IVcriterion (Diagnostic and Statistical Manual of Mental Disorders, fourth edition), and the intensity of psychotic manifestations was evaluated by using Brief Psychiatric Rating Scale (BPRS). The size of the caudate nucleus was determined on axial non-contrast CT images on the surface of the largest cross-section using AutoCAD 2007 digital morphometry. The statistical data were processed by the SPSS 16.0 program package. The statistical conclusions are presented on the basis of two-tail p < 0.05. Results: In this study, we have observed a negative correlation between the area as well as the perimeter of the left caudate nucleus head section and the intensity of the psychotic manifestations (area: regression coefficient B = –0.17, p = 0.050, perimeter: regression coefficient B = –0.010, p = 0.012). On the right hemisphere of the brain we observed only a negative correlation of the intensity of the psychotic manifestations from the perimeter of the head section of caudate nucleus (regression coefficient B = –0.013, p = 0.011). Conclusion: In our research we found that the higher intensity of psychotic manifestations in schizophrenia was accompanied with the smaller area and the perimeter of left caudate head as well as the smaller perimeter of the head of right caudate nucleus. The finding of the dependence of the intensity of psychotic manifestations on the perimeter of the right caudate head and not on its area speaks in favor of the caudate head surface deformations as one of the markers of intensity of psychotic manifestations in patients with schizophrenia.


INTRODUCTION
One of the significant functional disorders of the central nervous system in patients with schizophrenia is the increased activity of the mesolimbic dopaminergic system (1,2).Caudate nucleus belongs to the subcortical gray masses of the brain i.e.to basal ganglia.By the nigrostriatal pathway, the caudate nucleus is closely related to other dopaminergic systems of the brain.Since the function of caudate nucleus relies on the action of dopamine in the brain; the role of this anatomical structure in the pathogenesis of schizophrenia is not sufficiently clarified.The aim of this paper was to examine whether the caudate nucleus participates in the modulation of the intensity of psychotic manifestations in schizophrenia.

PATIENTS AND METHODS
The study encompassed a total of thirty-one persons with schizophrenia (F20): 15 females and 16 males.Schizophrenia diagnosis was based on the DSM-IV criterion (3), and the intensity of psychotic manifestations was evaluated using the Brief Psychiatric Rating Scale (BPRS) (4).The intensity of psychotic manifestations in this scale is scored by the values from 1 to 7 (1 = symptoms not present, 2 = very mild, 3 = mild, 4 = moderate, 5 = moderately strong, 6 = strong and 7 = extremely strong).More BPRS score values reflect higher intensity of the psychotic manifestations.
The size of the caudate nucleuswas determined on axial non-contrast CT images (layer thickness of 5 mm) on the surface of the largest cross section.The area and the perimeter of the caudate head were determined using the AutoCAD digital planimetry (Figure 1).AutoCAD 2007 for PC Windows (developed by Autodesk, Inc.San Rafael, California, U.S.) belongs to a group of software packages designed for drawing, designing and other aspects of computer application engineering practice.This software package can also be used to measure surfaces of irregular geometric figures, such as central nervous system structures (5).
Patients with severe comorbid states (cardiac decompensation, unstable angina pectoris, myocardial infarction in the previous and the year of the study, infectious diseases, malignant and chronic immune diseases) were excluded from the study because of the confounding effect.Also, the study did not include patients with other psychiatric disorders diagnoses, neurological disorders and patients with the history of stroke.
The statistic data are processed in the SPSS 16.0 program package.The hypotheses of the regression models used were tested.The statistical conclusions are presented on the basis of two-tail p < 0.05.

RESULTS
Examination of the correlationbetween intensity of psychotic manifestations in patients with schizophrenia comparing the gender and age of respondents is shown in Table 1.
Since the deviation of BPRS scores from the normal distribution was observed (Shapiro-Wilk test p = 0.044), in the correlation of psychotic manifestations intensityregarding the gender and age of respondents the generalized linear model of the subclass gamma with the log link (robust estimator) was used.Negative correlation i.e. higher intensity of symptoms of psychotic manifestations in younger personswas observed(regression coefficient B = -0.00036,p < 0.001) (Table 1).By incorporating only one parameter i.e. age of the respondents in the examined model, the aforementioned correlation was also confirmed (regression coefficient B = -0.00040,p < 0.001).
Examining the correlation of the intensity of psychotic manifestations (BPRS score) of patients with  schizophrenia and the age and the area of the largest cross section of the left caudate nucleus head we found greater intensity of psychotic manifestations in persons with smaller caudate head area (regression coefficient B = -0.17,p = 0.050) (Table 2).For the examination of statistical significance, the generalized linear model of the subclass gamma with the log link (robust estimator) was used.
Examining the correlation between intensity of psychotic manifestations (BPRS score) of patients with schizophrenia and the age and the perimeter of the largest cross section of the left caudate nucleus head we found greater intensity of psychotic manifestations in younger persons (regression coefficient B = -0.00047,p < 0.001) with smaller caudate head perimeter (regression coefficient B = -0.010,p = 0.012) (Table 3).For the examination of statistical significance, the generalized linear model of the subclass gamma with the log link (robust estimator) was used.
Examining the correlation between the intensity of psychotic manifestations (BPRS score) of patients with schizophrenia and the age and the area of the largest cross section of the right caudate nucleus head we did not certain correlation between the intensity of psychotic manifestations and caudate head area (regression coefficient B = -0.002,p = 0.404) (Table 4).For the examination of statistical significance, the generalized linear model of the subclass gamma with the log link (robust estimator) was used.
Examining the correlation between the intensity of psychotic manifestations (BPRS score) of patients with schizophrenia and the age and the perimeter of  the largest cross section of the right caudate nucleus head we found greater intensity of psychotic manifestations in younger persons(regression coefficient B = -0.0005,p < 0.001) with smaller caudate head perimeter (regression coefficient B = -0.013,p = 0.011) (Table 5).For the examination of statistical significance, the generalized linear model of the subclass gamma with the log link (robust estimator) was used.

DISCUSSION
In terms of morphology of caudate nucleus and its association with psychotic manifestations in schizophrenia results in the literature are different.Thus, for example, Rich AM et al. did not observe the morphometric caudate nucleus alterations in patients with chronic and early schizophrenia (6).Brugger SP et.Howes OD in meta-analysis also did not indicate the modified caudate nucleus in patients with the first episode of schizophrenia (7).Authors(8) came up with a similar conclusion.On the other hand, Ebdrup BH et al. indicated a reduction in volume and smaller caudate nucleus in patients with the first episode of schizophrenia without the use of antipsychotics (9).Also, Stegmayer K et al. in patients with schizophrenia and significant emotional dysregulation indicate the reduction of gray mass in ventral striatum and caudate nucleus (10).Li Y et al. in meta-analysis showed reduction of grey mass of the left caudate nucleus (11), and Brandt GN et Bonelli RM (12) emphasize, besides the reduction of caudate nucleus in the first episode of schizophrenia, to the increased caudate nucleus in chronic phase, as a consequence of the antipsychotic application.
The authors (13) also point out to the smaller caudate nucleus in early schizophrenia in comparison to a healthy population, with a subsequent increase in the  size of the caudate nucleus after ordering antipsychotic therapy.Zampieri E et al. emphasize the importance of antipsychotics to the increase of caudate nucleus too (14).However, in this case, different findings are also depicted in the literature.Emsley R et al. do not only challenge the smaller caudate nucleus in patients with early schizophrenia, pointing to their findings of a larger caudate nucleus of schizophrenic patients, but also negating the increase of the caudate nucleus after administration of antipsychotics such as risperidone and flupentixol (15).In support of the aforementioned larger caudate nucleus in patient with schizophrenia refer also the studies (16,17).Regarding the increase of caudate nucleus after ordering antipsychotics, Mouchlianitis E et al. cited different findings in meta-analysis i.e. three studies where antipsychotic clozapine led to caudate nucleus reduction, not increment (18).However, in the later case, there are literature counterparts that point to the increased metabolism of caudate nucleus after the administration of clozapine (19).So, the issues are not completely settled yet.
In our study, we found a negative correlation between intensity psychotic manifestations from the size of the cross section of caudate nucleus head; on the left brain hemisphere from the both i.e. area and perimeter (Table 2 and 3), and from the perimeter on the right brain side (Table 5).Greater intensity of psychotic manifestations in patients with smaller head size of cauda-te nucleus was also noted by the authors (20).Our finding of the dependence of the intensity of psychotic manifestations on the perimeter of the right caudate head and not from its area speaks in favor of the deformations of the surface of caudate nucleus head in patients with schizophrenia, as indicated by the study (21).

CONCLUSION
In our research we found that the higher intensity of psychotic manifestations in schizophrenia was accompanied with the smaller area and the perimeter of left caudate head as well as the smaller perimeter of the head of right caudate nucleus.The finding of the correlation between intensity of psychotic manifestations on the perimeter of the right caudate head and not on its area speaks in favor of the caudate head surface deformations as one of the markers of intensity of psychotic manifestations in patients with schizophrenia.

Figure 1 .
Figure 1.Display of the AutoCAD digital morphometry of the largest cross-section of the right caudate nucleus head: area 141.18 mm2, perimeter 48.802 mm

Table 1 .
Dependence of the intensity of psychotic manifestations of patients with schizophr enia regarding the gender and the age of respondents b BPRS: Brief Psychiatric Rating Scale Dependent Variable: BPRS score a.This parameter is set to zero because it is redundant.b.Calculation based on thePearson's Chi-Squared test.

Table 2 .
CORRELATION ANALYSIS BETWEEN THE MORPHOMETRIC CHARACTERISTICS OF THE HEAD OF NUCLEUS... 155 Examination of the dependency of the intensity of psychotic manifestations from the largest cross section area of the left caudate nucleus head a BPRS: Brief Psychiatric Rating Scale Dependent Variable: BPRS score a. Calculation based on thePearson's Chi-Squared test.

Table 3 .
Examination of the dependency of the intensity of psychotic manifestations from the largest cross section perimeter of the left caudate nucleus head a BPRS: Brief Psychiatric Rating Scale Dependent Variable: BPRS score a. Calculation based on thePearson's Chi-Squared test.

Table 4 .
Examination of the dependency of the intensity of psychotic manifestations from the largest cross section area of the right caudate nucleus head

Table 5 .
Examination of the dependency of the intensity of psychotic manifestations from the largest cross section perimeter of the right caudate nucleus head a BPRS: Brief Psychiatric Rating Scale Dependent Variable: BPRS score a. Calculation based on thePearson's Chi-Squared test.