# 2008 The Authors Journal compilation # 2008 Blackwell Munksgaard
Acta Neuropsychiatrica 2008: 20: 193–198 All rights reserved DOI: 10.1111/j.1601-5215.2008.00296.x
ACTA NEUROPSYCHIATRICA
Absence and size of massa intermedia in patients with schizophrenia and bipolar disorder Ceyhan M, Adapınar B, Aksaray G, Ozdemir F, Colak E. Absence and size of massa intermedia in patients with schizophrenia and bipolar disorder. Objective: To evaluate the absence and size of massa intermedia (MI), a midline thalamic structure, and its gender-specific alteration in patients with schizophrenia and bipolar disorder. Methods: Thirty-five patients with schizophrenia (17 females and 18 males), 21 patients with bipolar disorder (15 females and 6 males) and 89 healthy controls (50 females and 39 males) were evaluated by magnetic resonance imaging. Thin-slice magnetic resonance images of the brain were evaluated. MI was determined in coronal and sagittal images, and area of the MI was measured on the sagittal plane. Results: Females had a significantly lower incidence of absent MI compared with males in the healthy control group. The absence of MI in schizophrenia and bipolar patients was not higher than the incidence in healthy controls. The size of MI showed a gender difference. The mean MI area size was smaller in female schizophrenia patients than in female controls, while no significant difference was observed between male schizophrenia patients and their controls. Conclusions: The size of MI, a gender difference midline structure, is smaller in females with schizophrenia, and the results of this study support other studies of structural aberration of the thalamus and other midline structures in the brains of patients with schizophrenia.
Introduction
Massa intermedia (MI) is a midline thalamic structure connecting the two thalami within crossing organised axons. MI may sometimes be multiple, and its anteroposterior dimension measures about 1 cm (1). MI is well developed in mammals and contains several nuclei (2). In postmortem studies, the incidence of MI absence has been documented in 20–30% of normal human brains (3,4). Furthermore, the presence and variability of size are sexually dimorphic. MI is more often present in females than in males (5–7). Allen and Gorski showed in a post-mortem study that the area of the MI is larger in women compared with men (7). Recent studies report an association between midline morphologic cerebral abnormalities of brain (cavum septum pellucidum, agenesis of corpus callosum (CC), enlarged third ventricle, cerebellar vermis and absence of MI) and schizophrenia (8–
Meltem Ceyhan1, Baki Adapınar2, Gokay Aksaray3, Figen Ozdemir3, Ertugrul Colak4 1 Department of Radiology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey; 2 Department of Radiology, Faculty of Medicine, Osmangazi University, Eskisxehir, Turkey; 3Department of Psychiatry, Faculty of Medicine, Osmangazi University, Eskisxehir, Turkey; and 4Department of Biostatistics, Faculty of Medicine, Osmangazi University, Eskisxehir, Turkey
Keywords: bipolar disorder; gender differences; magnetic resonance imaging; massa intermedia; schizophrenia Meltem Ceyhan, Department of Radiology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey. Tel: 1903624576000/2541; Fax: 1903624576041; E-mail: [email protected]
16). It was suggested that the variety of symptoms seen in schizophrenia could be attributable to these abnormalities of midline neural circuits (17). Furthermore, the thalamus is involved in cognitive processes such as attention, which can be impaired not only in schizophrenia (18–20) but also in bipolar disorders (21,22), suggesting that there may be functional or anatomical abnormalities. In this study, incidence of absence and size of MI in patients with schizophrenia and bipolar disorder was compared with a control group taking in consideration the gender differences for each group.
Materials and methods Subjects
Thirty-five patients with schizophrenia (18 males and 17 females) and 21 patients with bipolar disorder (6 males and 15 females) diagnosed 193
Ceyhan et al. according to Diagnostic Statistical Manual-IV criteria were included in this study. Symptom data were obtained from the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in patients with schizophrenia (23). Mood symptoms were assessed in bipolar patients with the application of the Young Mania Rating Scale (24). Patients recruited through consecutive admissions to the Psychiatry Department of Faculty of Medicine of Osmangazi University were included in the study. The mean age of the schizophrenia patients was 37.6 11.2 years, and the mean onset age of the illness was 25 8.0 years. The mean age of the bipolar disorder patients was 32 10.3 years, and the mean onset age of the disease was 22.2 4.9 years. Eighty-nine volunteers were selected as the healthy control group (50 female and 39 male; mean age 36.6 1.28 years). Those with firstdegree relatives with any history of psychiatric illness or on psychiatric medication were not included in the study. Patients and/or controls were excluded if they had a history of epilepsy, head injury or other neurological disorders and medical illness. An informed consent was given by all the patients and/or patients relative and control subjects who were included in the study.
from Ml size analysis. MI area measurements in both groups were analysed using nonparametric Kruskall–Wallis analysis of variance and Bonferroniadjusted Mann–Whitney U-test because the data did not match normal distribution. Significances in chi-squared test and Kruskal–Wallis analysis of variance were accepted at p , 0.05, and Bonferroniadjusted Mann–Whitney U-test was accepted at p , 0.016. Student’s t-tests were used to search correlations between the presence or the absence of MI and clinical symptoms (age, duration of illness and scores on the SANS and SAPS). Spearman’s rho correlation coefficient was used to test correlations between areas of MI and clinical symptoms.
Results
According to MRI findings, patients with schizophrenia and bipolar disorder and the control
Methods
All cases were studied on coronal and sagittal planes by using 1.5 T magnetic resonance imaging (MRI) (Magneton Vision; Siemens, Erlangen, Germany) with the protocol T1-fl2d, TR ¼ 30, TE ¼ 6, flip angle ¼ 40°, NEX ¼ 2, thickness: 1 mm, matrix: 128 3 128 and FOV ¼ 210. The presence or absence of MI was determined in the cranial MRI taken in the coronal and sagittal planes in contiguous slices (Figs 1 and 2), and area of MI was measured in the midsagittal image (Fig. 2b). The MI was defined in MRI as an interthalamic adhesion located between the two adjacent thalami. When the MI could not be identified on coronal and sagittal adjacent slices, the MI was considered absent. Area of MI was measured on the midsagittal planes (because the visualisation of septum pellucidum defines midsagittal section) by manually tracing. The MRI images were assessed by a consensus between two radiologists. Statistical analysis
Chi-squared test was used for comparison of the absence or presence of MI between patient and control groups. MI-absent patients were excluded 194
Fig. 1. Absence of MI on coronal (a) and saggital (b) T1weighted images.
Massa intermedia in schizophrenia Table 2. The percentage of distribution of MI area averages in schizophrenia patients, bipolar disorder patients and control group Mean MI area (cm2) All schizophrenics All bipolar disorders All controls Male schizophrenics Male bipolar disorders Male controls Female schizophrenics Female bipolar disorders Female controls
0.58 0.76 0.90 0.74 0.55 0.83 0.40 0.81 0.93
0.45 0.53 0.55 0.53 0.50 0.57 0.26* 0.54 0.54*
MW U ¼ 711.5, p ¼ 0.008
w2KW ¼ 0.91, d.f. ¼ 2, p . 0.05
*MW U ¼ 118.5, p ¼ 0.001.
The presence and absence of MI
Fig. 2. Presence of MI on coronal (a) and saggital (b) T1weighted images. Measurement of the MI area on saggital T1weighted image (b).
groups were evaluated for the incidence of absent MI and MI area measurements by considering sexual difference (Tables 1 and 2), and the control groups were matched with the patients by age and gender. Table 1. The percentage of distribution of MI's presence–absence and MI area averages in schizophrenia patients, bipolar disorder patients and control group MI MI presence, absence, n (%) n (%) All schizophrenics All bipolar disorders All controls Male schizophrenics Male bipolar disorders Male controls Female schizophrenics Female bipolar disorders Female controls
28 18 77 15 4 30 13 14 47
(80.0) (85.7) (86.5) (83.3) (66.7) (76.9) (76.5) (93.3) (94.0)
7 3 12 3 2 9 4 1 3
(20.0) w2 ¼ 0.84, d.f. ¼ 2, p . 0.05 (14.3) (13.5) (16.7) w2 ¼ 0.76, d.f. ¼ 2, p . 0.05 (33.3) (23.1) (23.5) w2 ¼ 4.62, d.f. ¼ 2, p . 0.05 (6.7) (6.0)
The MI was absent in 13.5% of the healthy controls, and females had a significantly lower incidence of absent MI (6%) compared with males (23.1%) [(w2 ¼ 4.11, d.f. ¼ 1, p ¼ 0.04, OR ¼ 4.7 (1.04 R , 28.64)]. Comparison between the schizophrenia patients, bipolar patients and control subjects showed the incidence of absent MI to be 20% in schizophrenia patients, 14.3% in bipolar patients and 13.5% in healthy controls. Statistically, no significant difference was observed between the groups (w2 ¼ 0.84, d.f. ¼ 2, p . 0.05). Results evaluated according to sexual differences showed the incidence of absent MI to be 16.7% in male schizophrenia patients, 33.3% in male bipolar patients and 23.1% in male controls, which was not statistically significant (w2 ¼ 0.76, d.f. ¼ 2, p . 0.05). When incidence of absent MI was compared between females with schizophrenia (23.5%), female bipolar patients (6.7%) and female controls (6%), statistically there was no significant difference (w2 ¼ 4.62, d.f. ¼ 2, p . 0.05) between the groups (Table 1). MI size
In healthy controls, the mean measurement of MI area (cm2) was 0.93 0.54 in females and 0.83 0.57 in males, which was not a statistically significant difference (MW U, p ¼ 0.283). MI size had a negative correlation with age (Spearman’s rho correlation coefficient r ¼ 20.463, p ¼ 0.00002) in the control group. The mean MI area (cm2) in schizophrenia patients was 0.58 45, 0.76 0.53 in patients with bipolar disorder and 0.90 0.55 in the control group. Significant differences between the three groups (w2KW ¼ 7.12, d.f. ¼ 2, p ¼ 0.028) were seen. MI area was smaller in patients with schizophrenia (MW U, p ¼ 0.008) when compared with the controls. No significant difference was 195
Ceyhan et al. observed between male schizophrenics, male bipolar patients and male controls (w2KW ¼ 0.91, d.f. ¼ 2, p . 0.05), although there was a significant difference between the three female groups (w2KW ¼ 11.0, d.f. ¼ 2, p , 0.004). MI area was lower in female schizophrenics compared with their controls (MW U, p ¼ 0.001) (Table 2).
MI and clinical relations
There were no significant differences between schizophrenia patients with MI and those without MI in regard to age (Student’s t-test, p ¼ 0.707), age at onset of illness (Student’s t-test, p ¼ 0.588), duration of illness (Student’s t-test, p ¼ 0.985) and score on the SANS (MW U, p ¼ 0.869) and the SAPS (MW U, p ¼ 0.234). There was also no significant difference between bipolar disorder patients missing MI and those with MI in age (MW U, p ¼ 0.650), age at onset of illness (MW U, p ¼ 0.246), duration of illness (MW U, p ¼ 0.762) and scores on the Young Mania Rating Scale (MW U, p ¼ 0.312). MI size had a negative correlation with age (Spearman’s rho correlation coefficient r ¼ 20.422, p ¼ 0.025) and duration of illness (Spearman’s rho correlation coefficient r ¼ 20.403, p ¼ 0.033) but no correlation with SANS (Spearman’s rho correlation coefficient r ¼ 20.058, p ¼ 0.770), SAPS (Spearman’s rho correlation coefficient r ¼ 20.217, p ¼ 0.267) or age at onset of illness (Spearman’s rho correlation coefficient r ¼ 20.106, p ¼ 0.592) in schizophrenia patients. In patients with bipolar disorder, no correlation was found between MI area and age (Spearman’s rho correlation coefficient r ¼ 20.078, p ¼ 0.758), age at onset of illness (Spearman’s rho correlation coefficient r ¼ 20.277, p ¼ 0.266) and duration of illness (Spearman’s rho correlation coefficient r ¼ 0.096, p ¼ 0.704).
Discussion
The clinical and physiologic importance of midbrain structures has been a popular research interest in neurosciences, particularly following the widespread use of imaging methods. The MRI findings of recently published studies show that MI may be absent in approximately 10–20% of the healthy subjects, and the results of this study support this conclusion (4,12,25). Other studies have reported significant gender-related differences regarding the presence of MI with higher incidence in women than in men (5–7,25). Furthermore, Allen and Gorski reported that the MI area was 196
larger in women than in men (7). Our findings regarding MI frequency in women were similar providing further support for their conclusions, although MI area was larger in women, but this was statistically not significant. The functional significance of MI is not well known; however, some hypotheses propose that brain function in women, especially with respect to language capability, is more symmetrical than in men. This theory is supported by studies performed in stroke patients where language disorders are more pervasive in men than in women after a left hemisphere stroke (25,26). Because MI connects the two thalami functionally and is more often present in women, this could be related to the more bilateral organisation of language function in women compared with men (25). Many of the structural brain abnormalities in the midline or medial region of the brain such as the CC (27,28), septum pellucidum (9,10,13,29) and cerebellar vermis (30,31) were reported in patients with schizophrenia. It was suggested that abnormal midline neuronal transmission of information is one of the pathologic reasons in the formation of clinical symptoms of schizophrenia (17). MI could play a role in the pathophysiology of schizophrenia because of its anatomical localisation in midline brain and subregion of thalamus (25). Some MRI studies show that the incidence of MI absence is more frequent in patients with schizophrenia than in healthy subjects (11,12). Although the incidence of absent MI was higher in schizophrenia patients compared with controls in our study, the difference was not statistically significant (20% in schizophrenics and 13.5% in controls). This is in line with the non-significant results of other MRI studies by Meisenzahl et al. (32), Nopoulos et al. (25) and Crippa et al. (13). In a recent report by Ettinger et al. who investigated the presence of the MI in monozygotic twins concordant or discordant for schizophrenia, there was no difference across the groups (20). In addition to these, Nopoulos et al. showed that female patients with schizophrenia had a significantly higher prevalence of absent MI compared with female controls (25). Although, the absence of MI was more prevalent in female schizophrenics in our study, no statistically significant difference was observed. In a study by Meisenzahl et al., absence of MI in schizophrenia was significantly correlated with the presence of negative symptoms (32). Despite this finding, other studies by Nopoluos et al. (25), Erbagci et al. (12) and Crippa et al. (13) did not show a significant difference between patients with MI and those without MI in regard to clinical
Massa intermedia in schizophrenia variables. Also in this study, there was no significant correlation between positive and negative symptoms regarding the presence or absence of MI in schizophrenia patients. Although the size of MI is directly related with ageing in normal population and patients with schizophrenia as clearly seen in our data, there is also a significant association between reduced size of MI and the duration of illness regardless the age of schizophrenia. Several volumetric studies using MRI have showed progressive structural changes in schizophrenia that may even seen in the first episode (33–35). Some studies suggest that there are progressive brain changes throughout the course of the illness (36–38). This could be directly related to the use of antipsychotic medication or to the impact of psychosis itself. Additionally in this study, the role of MI size in schizophrenia by measuring the area of MI on the sagittal planes of MRI was investigated. According to our results, we found that female schizophrenics were more likely to have small MI compared with their controls, whereas no difference in the size of MI was found between male patients and their controls. Similarly, Hoff et al. observed a significant gender difference in the size of CC – a midline brain structure as MI – and a higher decrease of volume in female patients (39). This finding was supported by the post-mortem study of Highly et al. evaluating the size and fibre composition of the CC in schizophrenics and in controls, and they reported that females had a greater density of CC fibres (40). In our study, we evaluated additionally the MI size and presence in patients with bipolar disorder as well as in schizophrenia patients. In the previous medical literature, cranial imaging findings in bipolar disorder patients including white matter hyperintensities, decreased cerebellar size, increased sulcal prominence and enlargement of the lateral and third ventricles were reported (41). To the best of our knowledge, no study looked at the MI in patients with bipolar disorder up to date in the literature. However, Blumberg et al. observed a conspicuous increase in the signal on thalamus in the functional MR studies when those with bipolar disorder were compared with a control group (42). Furthermore, Dasari et al. observed a significant decrease in the sizes of the thalamic fields in these patients (43). However, in contrast to these studies, Caetano et al. observed no thalamic abnormality in bipolar disorder (44). According to our results, no correlation was seen between the absence/sizes of MI and bipolar disorder, although the sample number is too small for firm conclusions.
In summary, this study showed that the MI is a gender dimorphic midline structure in the brain of people with schizophrenia. In patients with schizophrenia, size of MI is dependent on sex: smaller in female patients compared with their controls, whereas no difference in the size of MI was found between male patients and their controls. The size of MI might play a role in the pathophysiology of schizophrenia. However, the determination of structural abnormalities alone provides limited information in the understanding of the pathophysiology of these diseases, and more structural and functional studies are required on this subject.
Acknowledgement Authors are grateful to Professor Dr Levent Doganci from OMU Medical School for reviewing the manuscript and his suggestion in english grammar.
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Acta Neuropsychiatrica 2008: 20: 193–198 All rights reserved DOI: 10.1111/j.1601-5215.2008.00296.x
ACTA NEUROPSYCHIATRICA
Absence and size of massa intermedia in patients with schizophrenia and bipolar disorder Ceyhan M, Adapınar B, Aksaray G, Ozdemir F, Colak E. Absence and size of massa intermedia in patients with schizophrenia and bipolar disorder. Objective: To evaluate the absence and size of massa intermedia (MI), a midline thalamic structure, and its gender-specific alteration in patients with schizophrenia and bipolar disorder. Methods: Thirty-five patients with schizophrenia (17 females and 18 males), 21 patients with bipolar disorder (15 females and 6 males) and 89 healthy controls (50 females and 39 males) were evaluated by magnetic resonance imaging. Thin-slice magnetic resonance images of the brain were evaluated. MI was determined in coronal and sagittal images, and area of the MI was measured on the sagittal plane. Results: Females had a significantly lower incidence of absent MI compared with males in the healthy control group. The absence of MI in schizophrenia and bipolar patients was not higher than the incidence in healthy controls. The size of MI showed a gender difference. The mean MI area size was smaller in female schizophrenia patients than in female controls, while no significant difference was observed between male schizophrenia patients and their controls. Conclusions: The size of MI, a gender difference midline structure, is smaller in females with schizophrenia, and the results of this study support other studies of structural aberration of the thalamus and other midline structures in the brains of patients with schizophrenia.
Introduction
Massa intermedia (MI) is a midline thalamic structure connecting the two thalami within crossing organised axons. MI may sometimes be multiple, and its anteroposterior dimension measures about 1 cm (1). MI is well developed in mammals and contains several nuclei (2). In postmortem studies, the incidence of MI absence has been documented in 20–30% of normal human brains (3,4). Furthermore, the presence and variability of size are sexually dimorphic. MI is more often present in females than in males (5–7). Allen and Gorski showed in a post-mortem study that the area of the MI is larger in women compared with men (7). Recent studies report an association between midline morphologic cerebral abnormalities of brain (cavum septum pellucidum, agenesis of corpus callosum (CC), enlarged third ventricle, cerebellar vermis and absence of MI) and schizophrenia (8–
Meltem Ceyhan1, Baki Adapınar2, Gokay Aksaray3, Figen Ozdemir3, Ertugrul Colak4 1 Department of Radiology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey; 2 Department of Radiology, Faculty of Medicine, Osmangazi University, Eskisxehir, Turkey; 3Department of Psychiatry, Faculty of Medicine, Osmangazi University, Eskisxehir, Turkey; and 4Department of Biostatistics, Faculty of Medicine, Osmangazi University, Eskisxehir, Turkey
Keywords: bipolar disorder; gender differences; magnetic resonance imaging; massa intermedia; schizophrenia Meltem Ceyhan, Department of Radiology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey. Tel: 1903624576000/2541; Fax: 1903624576041; E-mail: [email protected]
16). It was suggested that the variety of symptoms seen in schizophrenia could be attributable to these abnormalities of midline neural circuits (17). Furthermore, the thalamus is involved in cognitive processes such as attention, which can be impaired not only in schizophrenia (18–20) but also in bipolar disorders (21,22), suggesting that there may be functional or anatomical abnormalities. In this study, incidence of absence and size of MI in patients with schizophrenia and bipolar disorder was compared with a control group taking in consideration the gender differences for each group.
Materials and methods Subjects
Thirty-five patients with schizophrenia (18 males and 17 females) and 21 patients with bipolar disorder (6 males and 15 females) diagnosed 193
Ceyhan et al. according to Diagnostic Statistical Manual-IV criteria were included in this study. Symptom data were obtained from the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in patients with schizophrenia (23). Mood symptoms were assessed in bipolar patients with the application of the Young Mania Rating Scale (24). Patients recruited through consecutive admissions to the Psychiatry Department of Faculty of Medicine of Osmangazi University were included in the study. The mean age of the schizophrenia patients was 37.6 11.2 years, and the mean onset age of the illness was 25 8.0 years. The mean age of the bipolar disorder patients was 32 10.3 years, and the mean onset age of the disease was 22.2 4.9 years. Eighty-nine volunteers were selected as the healthy control group (50 female and 39 male; mean age 36.6 1.28 years). Those with firstdegree relatives with any history of psychiatric illness or on psychiatric medication were not included in the study. Patients and/or controls were excluded if they had a history of epilepsy, head injury or other neurological disorders and medical illness. An informed consent was given by all the patients and/or patients relative and control subjects who were included in the study.
from Ml size analysis. MI area measurements in both groups were analysed using nonparametric Kruskall–Wallis analysis of variance and Bonferroniadjusted Mann–Whitney U-test because the data did not match normal distribution. Significances in chi-squared test and Kruskal–Wallis analysis of variance were accepted at p , 0.05, and Bonferroniadjusted Mann–Whitney U-test was accepted at p , 0.016. Student’s t-tests were used to search correlations between the presence or the absence of MI and clinical symptoms (age, duration of illness and scores on the SANS and SAPS). Spearman’s rho correlation coefficient was used to test correlations between areas of MI and clinical symptoms.
Results
According to MRI findings, patients with schizophrenia and bipolar disorder and the control
Methods
All cases were studied on coronal and sagittal planes by using 1.5 T magnetic resonance imaging (MRI) (Magneton Vision; Siemens, Erlangen, Germany) with the protocol T1-fl2d, TR ¼ 30, TE ¼ 6, flip angle ¼ 40°, NEX ¼ 2, thickness: 1 mm, matrix: 128 3 128 and FOV ¼ 210. The presence or absence of MI was determined in the cranial MRI taken in the coronal and sagittal planes in contiguous slices (Figs 1 and 2), and area of MI was measured in the midsagittal image (Fig. 2b). The MI was defined in MRI as an interthalamic adhesion located between the two adjacent thalami. When the MI could not be identified on coronal and sagittal adjacent slices, the MI was considered absent. Area of MI was measured on the midsagittal planes (because the visualisation of septum pellucidum defines midsagittal section) by manually tracing. The MRI images were assessed by a consensus between two radiologists. Statistical analysis
Chi-squared test was used for comparison of the absence or presence of MI between patient and control groups. MI-absent patients were excluded 194
Fig. 1. Absence of MI on coronal (a) and saggital (b) T1weighted images.
Massa intermedia in schizophrenia Table 2. The percentage of distribution of MI area averages in schizophrenia patients, bipolar disorder patients and control group Mean MI area (cm2) All schizophrenics All bipolar disorders All controls Male schizophrenics Male bipolar disorders Male controls Female schizophrenics Female bipolar disorders Female controls
0.58 0.76 0.90 0.74 0.55 0.83 0.40 0.81 0.93
0.45 0.53 0.55 0.53 0.50 0.57 0.26* 0.54 0.54*
MW U ¼ 711.5, p ¼ 0.008
w2KW ¼ 0.91, d.f. ¼ 2, p . 0.05
*MW U ¼ 118.5, p ¼ 0.001.
The presence and absence of MI
Fig. 2. Presence of MI on coronal (a) and saggital (b) T1weighted images. Measurement of the MI area on saggital T1weighted image (b).
groups were evaluated for the incidence of absent MI and MI area measurements by considering sexual difference (Tables 1 and 2), and the control groups were matched with the patients by age and gender. Table 1. The percentage of distribution of MI's presence–absence and MI area averages in schizophrenia patients, bipolar disorder patients and control group MI MI presence, absence, n (%) n (%) All schizophrenics All bipolar disorders All controls Male schizophrenics Male bipolar disorders Male controls Female schizophrenics Female bipolar disorders Female controls
28 18 77 15 4 30 13 14 47
(80.0) (85.7) (86.5) (83.3) (66.7) (76.9) (76.5) (93.3) (94.0)
7 3 12 3 2 9 4 1 3
(20.0) w2 ¼ 0.84, d.f. ¼ 2, p . 0.05 (14.3) (13.5) (16.7) w2 ¼ 0.76, d.f. ¼ 2, p . 0.05 (33.3) (23.1) (23.5) w2 ¼ 4.62, d.f. ¼ 2, p . 0.05 (6.7) (6.0)
The MI was absent in 13.5% of the healthy controls, and females had a significantly lower incidence of absent MI (6%) compared with males (23.1%) [(w2 ¼ 4.11, d.f. ¼ 1, p ¼ 0.04, OR ¼ 4.7 (1.04 R , 28.64)]. Comparison between the schizophrenia patients, bipolar patients and control subjects showed the incidence of absent MI to be 20% in schizophrenia patients, 14.3% in bipolar patients and 13.5% in healthy controls. Statistically, no significant difference was observed between the groups (w2 ¼ 0.84, d.f. ¼ 2, p . 0.05). Results evaluated according to sexual differences showed the incidence of absent MI to be 16.7% in male schizophrenia patients, 33.3% in male bipolar patients and 23.1% in male controls, which was not statistically significant (w2 ¼ 0.76, d.f. ¼ 2, p . 0.05). When incidence of absent MI was compared between females with schizophrenia (23.5%), female bipolar patients (6.7%) and female controls (6%), statistically there was no significant difference (w2 ¼ 4.62, d.f. ¼ 2, p . 0.05) between the groups (Table 1). MI size
In healthy controls, the mean measurement of MI area (cm2) was 0.93 0.54 in females and 0.83 0.57 in males, which was not a statistically significant difference (MW U, p ¼ 0.283). MI size had a negative correlation with age (Spearman’s rho correlation coefficient r ¼ 20.463, p ¼ 0.00002) in the control group. The mean MI area (cm2) in schizophrenia patients was 0.58 45, 0.76 0.53 in patients with bipolar disorder and 0.90 0.55 in the control group. Significant differences between the three groups (w2KW ¼ 7.12, d.f. ¼ 2, p ¼ 0.028) were seen. MI area was smaller in patients with schizophrenia (MW U, p ¼ 0.008) when compared with the controls. No significant difference was 195
Ceyhan et al. observed between male schizophrenics, male bipolar patients and male controls (w2KW ¼ 0.91, d.f. ¼ 2, p . 0.05), although there was a significant difference between the three female groups (w2KW ¼ 11.0, d.f. ¼ 2, p , 0.004). MI area was lower in female schizophrenics compared with their controls (MW U, p ¼ 0.001) (Table 2).
MI and clinical relations
There were no significant differences between schizophrenia patients with MI and those without MI in regard to age (Student’s t-test, p ¼ 0.707), age at onset of illness (Student’s t-test, p ¼ 0.588), duration of illness (Student’s t-test, p ¼ 0.985) and score on the SANS (MW U, p ¼ 0.869) and the SAPS (MW U, p ¼ 0.234). There was also no significant difference between bipolar disorder patients missing MI and those with MI in age (MW U, p ¼ 0.650), age at onset of illness (MW U, p ¼ 0.246), duration of illness (MW U, p ¼ 0.762) and scores on the Young Mania Rating Scale (MW U, p ¼ 0.312). MI size had a negative correlation with age (Spearman’s rho correlation coefficient r ¼ 20.422, p ¼ 0.025) and duration of illness (Spearman’s rho correlation coefficient r ¼ 20.403, p ¼ 0.033) but no correlation with SANS (Spearman’s rho correlation coefficient r ¼ 20.058, p ¼ 0.770), SAPS (Spearman’s rho correlation coefficient r ¼ 20.217, p ¼ 0.267) or age at onset of illness (Spearman’s rho correlation coefficient r ¼ 20.106, p ¼ 0.592) in schizophrenia patients. In patients with bipolar disorder, no correlation was found between MI area and age (Spearman’s rho correlation coefficient r ¼ 20.078, p ¼ 0.758), age at onset of illness (Spearman’s rho correlation coefficient r ¼ 20.277, p ¼ 0.266) and duration of illness (Spearman’s rho correlation coefficient r ¼ 0.096, p ¼ 0.704).
Discussion
The clinical and physiologic importance of midbrain structures has been a popular research interest in neurosciences, particularly following the widespread use of imaging methods. The MRI findings of recently published studies show that MI may be absent in approximately 10–20% of the healthy subjects, and the results of this study support this conclusion (4,12,25). Other studies have reported significant gender-related differences regarding the presence of MI with higher incidence in women than in men (5–7,25). Furthermore, Allen and Gorski reported that the MI area was 196
larger in women than in men (7). Our findings regarding MI frequency in women were similar providing further support for their conclusions, although MI area was larger in women, but this was statistically not significant. The functional significance of MI is not well known; however, some hypotheses propose that brain function in women, especially with respect to language capability, is more symmetrical than in men. This theory is supported by studies performed in stroke patients where language disorders are more pervasive in men than in women after a left hemisphere stroke (25,26). Because MI connects the two thalami functionally and is more often present in women, this could be related to the more bilateral organisation of language function in women compared with men (25). Many of the structural brain abnormalities in the midline or medial region of the brain such as the CC (27,28), septum pellucidum (9,10,13,29) and cerebellar vermis (30,31) were reported in patients with schizophrenia. It was suggested that abnormal midline neuronal transmission of information is one of the pathologic reasons in the formation of clinical symptoms of schizophrenia (17). MI could play a role in the pathophysiology of schizophrenia because of its anatomical localisation in midline brain and subregion of thalamus (25). Some MRI studies show that the incidence of MI absence is more frequent in patients with schizophrenia than in healthy subjects (11,12). Although the incidence of absent MI was higher in schizophrenia patients compared with controls in our study, the difference was not statistically significant (20% in schizophrenics and 13.5% in controls). This is in line with the non-significant results of other MRI studies by Meisenzahl et al. (32), Nopoulos et al. (25) and Crippa et al. (13). In a recent report by Ettinger et al. who investigated the presence of the MI in monozygotic twins concordant or discordant for schizophrenia, there was no difference across the groups (20). In addition to these, Nopoulos et al. showed that female patients with schizophrenia had a significantly higher prevalence of absent MI compared with female controls (25). Although, the absence of MI was more prevalent in female schizophrenics in our study, no statistically significant difference was observed. In a study by Meisenzahl et al., absence of MI in schizophrenia was significantly correlated with the presence of negative symptoms (32). Despite this finding, other studies by Nopoluos et al. (25), Erbagci et al. (12) and Crippa et al. (13) did not show a significant difference between patients with MI and those without MI in regard to clinical
Massa intermedia in schizophrenia variables. Also in this study, there was no significant correlation between positive and negative symptoms regarding the presence or absence of MI in schizophrenia patients. Although the size of MI is directly related with ageing in normal population and patients with schizophrenia as clearly seen in our data, there is also a significant association between reduced size of MI and the duration of illness regardless the age of schizophrenia. Several volumetric studies using MRI have showed progressive structural changes in schizophrenia that may even seen in the first episode (33–35). Some studies suggest that there are progressive brain changes throughout the course of the illness (36–38). This could be directly related to the use of antipsychotic medication or to the impact of psychosis itself. Additionally in this study, the role of MI size in schizophrenia by measuring the area of MI on the sagittal planes of MRI was investigated. According to our results, we found that female schizophrenics were more likely to have small MI compared with their controls, whereas no difference in the size of MI was found between male patients and their controls. Similarly, Hoff et al. observed a significant gender difference in the size of CC – a midline brain structure as MI – and a higher decrease of volume in female patients (39). This finding was supported by the post-mortem study of Highly et al. evaluating the size and fibre composition of the CC in schizophrenics and in controls, and they reported that females had a greater density of CC fibres (40). In our study, we evaluated additionally the MI size and presence in patients with bipolar disorder as well as in schizophrenia patients. In the previous medical literature, cranial imaging findings in bipolar disorder patients including white matter hyperintensities, decreased cerebellar size, increased sulcal prominence and enlargement of the lateral and third ventricles were reported (41). To the best of our knowledge, no study looked at the MI in patients with bipolar disorder up to date in the literature. However, Blumberg et al. observed a conspicuous increase in the signal on thalamus in the functional MR studies when those with bipolar disorder were compared with a control group (42). Furthermore, Dasari et al. observed a significant decrease in the sizes of the thalamic fields in these patients (43). However, in contrast to these studies, Caetano et al. observed no thalamic abnormality in bipolar disorder (44). According to our results, no correlation was seen between the absence/sizes of MI and bipolar disorder, although the sample number is too small for firm conclusions.
In summary, this study showed that the MI is a gender dimorphic midline structure in the brain of people with schizophrenia. In patients with schizophrenia, size of MI is dependent on sex: smaller in female patients compared with their controls, whereas no difference in the size of MI was found between male patients and their controls. The size of MI might play a role in the pathophysiology of schizophrenia. However, the determination of structural abnormalities alone provides limited information in the understanding of the pathophysiology of these diseases, and more structural and functional studies are required on this subject.
Acknowledgement Authors are grateful to Professor Dr Levent Doganci from OMU Medical School for reviewing the manuscript and his suggestion in english grammar.
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