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Is cerebellar volume related to bipolar disorder?
Journal of Affective Disorders 135 (2011) 305–309
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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Preliminary communication
Is cerebellar volume related to bipolar disorder? L. Baldaçara a, b,⁎, F. Nery-Fernandes c, M. Rocha c, L.C. Quarantini c, G.G.L. Rocha d, J.L. Guimarães c, C. Araújo d, I. Oliveira c, A. Miranda-Scippa c, A. Jackowski b a b c d
Universidade Federal Tocantins, Tocantins, Brazil Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), Universidade Federal de São Paulo, São Paulo, Brazil Centro de Estudos de Transtornos de Humor e Ansiedade (CETHA), Universidade Federal da Bahia, Salvador, Bahia, Brazil Image Memorial, Medicina Diagnóstica, Salvador, BA, Brazil
a r t i c l e
i n f o
Article history: Received 7 June 2011 Accepted 29 June 2011 Available online 23 July 2011 Keywords: Bipolar disorder Cerebellum Magnetic Resonance Imaging Mood disorders Neurobiology
a b s t r a c t Background: Recent data suggest that cerebellum influences emotion modulation in humans. The findings of cerebellar abnormalities in bipolar disorder (BD) are especially intriguing given the link between the cerebellum emotional and behavioral regulation. The purpose of this study was to evaluate cerebellar volume in patients with euthymic BD type I compared to controls. Moreover, we investigated the possible relationship between cerebellar volume and suicidal behavior. Methods: Forty-patients with euthymic BD type I, 20 with and 20 without history of suicide attempt, and 22 healthy controls underwent an MRI scan. The participants were interviewed using the Structured Clinical Interview with the DSM-IV axis I (SCID-I), the Hamilton Depression Rating Scale (HDRS), the Young Mania Rating Scale (YMRS) and the Barratt Impulsiveness Scale (BIS-11). Results: Groups were age, gender and years of schooling-matched. The left cerebellum (p = 0.02), right cerebellum (p = 0.02) and vermis (p b 0.01) were significantly smaller in the BD group; however, there were no volumetric differences between the BD subjects with and without suicidal attempt. There was no correlation between cerebellar measurements and clinical variables. Limitations: The main strength is that our sample consisted of patients with euthymic BD type I without any comorbidities, however, these results cannot establish causality as the crosssectional nature of the study. Conclusions: Our findings suggest that the reduction in cerebellar volumes observed in BD type I might be a trait-related characteristic of this disorder. Additional studies with larger samples and subtypes of this heterogeneous disorder are warranted to determine the possible specificity of this cerebellar finding. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Structural imaging studies suggest that, although patients with BD exhibit relatively healthy-appearing brains overall,
⁎ Corresponding author at: Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), Edifício de Pesquisas II - UNIFESP, Rua Pedro de Toledo, 669 - 3° andar fundos, Vila Clementino - São Paulo, SP, CEP: 04039-032. Tel./fax: +55 11 5539 1468. E-mail address: [email protected] (L. Baldaçara). 0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2011.06.059
cortical and subcortical brain structures may be impaired. Cerebellar abnormalities go either way (i.e., volumes may be larger or smaller) in amygdala volume (Brambilla et al., 2003; Rosso et al., 2007), hippocampus (Aylward et al., 1994; Beyer et al., 2004; Blumberg et al., 2003), basal ganglia (Ahn et al., 2007; Bielau et al., 2005; Hwang et al., 2006), and prefrontal cortex (Najt et al., 2007; Sharma et al., 2003) are the most common findings in BD. However, these results are not consistent between studies. Multiple factors could contribute to the variability in these findings, including gender-related
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differences, volumetric changes related to the use of mood stabilizers, and genetic variation (Womer et al., 2009). Since the 1960s, studies have posited that the cerebellum plays a role in the experience and regulation of emotion (Nashold and Slaughter, 1969; Schutter and van Honk, 2009), and cerebellar findings have also been reported in BD. Cerebellar atrophy (Lippmann et al., 1982; Nasrallah et al., 1981, 1982; Weinberger et al., 1982), cerebellar gray matter reduction (Moorhead et al., 2007), and smaller vermal subregion V2 and V3 are the main findings in patients with BD (DelBello et al., 1999; Mills et al., 2005; Monkul et al., 2008). In this study, we use the region of interest (ROI) MRI approach to evaluate whether cerebellar volume in patients with euthymic BD type I is reduced as compared to healthy controls. In a second analysis, we assess the association between cerebellar volumes and suicidal behavior. 2. Methods 2.1. Participants We screened a total of 48 patients with euthymic BD type I and 25 healthy controls. Eight patients and three controls were excluded due to a history of neurological illness, head trauma, or inability to complete the MRI exam. Additional exclusion criteria included a lifetime history of substance abuse or a current, serious medical problem within the preceding 6 months. The final sample consisted of 40 patients with euthymic BD type I (20 with a history of suicide attempt and 20 without a history of suicide attempt) and 22 healthy controls. Patients were recruited from the Mood and Anxiety Program of the Federal University of Bahia and were interviewed using the Structured Clinical Interview for the DSM-IV axis I (SCID-I) (First et al., 2002), the Hamilton Depression Rating Scale (HDRS) (Hamilton, 1960), the Young Mania Rating Scale (YMRS) (Young et al., 1978), and the Barratt Impulsiveness Scale (BIS-11) (Bayle et al., 2000). The euthymia criterion was scores for both the YMRS and the HDRS under 7 points. Sociodemographical and clinical data were gathered through a questionnaire. Patients were classified as having positive suicidal history if they reported one or more self-injurious acts committed with the intent to die. Healthy controls were recruited from patient's social network. None of the healthy subjects had a current or previous history of Axis I DSM-IV psychiatric disorder or a first-degree relative with an Axis I psychiatric disorder. 2.2. Magnetic Resonance Imaging Imaging data were acquired at the Image Memorial Medicina Diagnóstica-Bahia-Brazil using a 1.5T Symphony Master/Class Siemens. Structural MR images were acquired using a sagittal T1 acquisition series (TR = 1850 ms, TE= 3.45 ms, flip angle = 13°, NEX = 1, matrix size = 256 × 256, FOV = 24 cm, thickness = 1.0 mm) rendering 160 slices. 2.3. Brain volume Brain volume was measured using voxel-based morphometry (VBM) methodology, as implemented via the VBM Toolbox
in SPM5 (dbm.neuro.uni-jena.de/vbm). This methodology has been described previously (Ashburner and Friston, 2005). The sum of all voxel values within the segmented image approximates the total volume within the corresponding partition. Total brain volume was computed from the sum of gray and white matter volumes (Ashburner and Friston, 2005). 2.4. Cerebellar volumes The cerebellar ROI tracing was performed using the Brains 2 semi-automated model and was manually corrected based on previous studies (Luft et al., 1999; Pierson et al., 2002). The cerebellar hemispheres and vermis were manually traced using protocols, which have been described elsewhere (De Bellis and Kuchibhatla, 2006; Luft et al., 1999; Pierson et al., 2002). The cerebellar ROI measurements began at the point that the cerebellum appeared lateral to the pons. The tentorium cerebelli were considered to be the superior limit of the cerebellum, while the base of the cerebellum itself was considered to be the inferior limit. The cisterna magna and transverse sinus were excluded (De Bellis and Kuchibhatla, 2006). The last slice included was the one at which the cerebellum was no longer distinguishable from the transverse sinus or was no longer visible. The vermis measurement started at the slice where the anterior and/or inferior posterior lobes appeared. Measurements were made until the vermis was no longer visible (De Bellis and Kuchibhatla, 2006). 2.5. Reproducibility To evaluate intra-rater reproducibility, same rater repeated the cerebellar measurements twice, at least 1 week apart, for ten randomly selected subjects. Intra-rater reliability was found to be high (ICC N0.96) for all cerebellar and vermal regions. 2.6. Data analysis Data were codified and analyzed using the Statistical Package for Social Sciences (SPSS for Windows, version 15.0). Prior to conducting analyses, measures were examined for normality using the Shapiro–Wilk test. The level of significance was set at p b 0.05 using a two-tailed test. Differences in proportion were compared using the chisquare test. Continuous variables were compared using Student's t-test and the Analysis of Variance (ANOVA). By employing the General Linear Model, analyses of covariance (ANCOVAs) were performed to investigate volume differences in the brain and cerebellar subregions across groups, after which Duncan's post hoc test was performed. The level of significance was set at p b 0.05 using a two-tailed test. 3. Ethical issues Participants who agreed to participate after the explanation of the study signed an informed consent form. The study was fully approved by the Institutional Ethics Committee of Federal University of Bahia (16/2005).
L. Baldaçara et al. / Journal of Affective Disorders 135 (2011) 305–309
4. Results There was no age, gender or years of schooling differences among patients with BD and healthy controls. The mean number of suicide attempts was 1.6 ± 0.8. There was no difference between patients with BD who exhibited suicidal behavior and those who did not in terms of age, gender, and years of schooling. For more details, see Table 1. BIS scores were higher in BD subjects with a history of suicide attempts (67.35 ± 14.80) as compared to both those without attempts (58.34 ± 8.64) and control group (58.52 ± 9.05) (p = 0.05). There were no differences in intracranial and brain volumes between the BD group and the healthy controls. The left cerebellum (p = 0.02), right cerebellum (p = 0.02) and vermis (p b 0.01) were smaller in the BD group (Table 2). Vermal volume was smaller in the BD group than the healthy control group (p b 0.01), although it was similar between the BD groups without and with suicide behavior groups. For more details, see Table 2. There was no correlation between vermal and cerebellar hemisphere volumes and BIS, number of suicide attempts, or number of mood episodes (manic, depressive or mixed episodes). 5. Discussion In this study, we examined anatomical abnormalities in the cerebellum of patients with euthymic BD type I compared to healthy controls. The volumes of the cerebellar hemispheres and the vermis were reduced in the BD group. However, there were no differences between BD subjects with and without a history of suicide attempts. The cerebellum is reciprocally connected to limbic structures, including the amygdala, hippocampus, septum, as well as the cerebral cortex, including prefrontal areas (Heath and Harper, 1974; Snider and Maiti, 1976). This feature provides a strong neuroanatomical basis for the involvement of the cerebellum in emotion regulation. As BD is a multi-state heterogeneous syndrome, a variety of neuroimaging findings are observed in the literature (Emsell and McDonald, 2009; Langan and McDonald, 2009; Liu et al., 2010; Mahon et al., 2009; Monkul et al., 2008). Early Computed Tomography (CT) studies have found cerebellar atrophy in patients with BD. The importance of these findings, however, was limited as only qualitative assessments were performed (Lippmann et al., 1982; Nasrallah et al., 1981, 1982;
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Weinberger et al., 1982). While cerebral atrophy was more frequent in patients with schizophrenia, cerebellar atrophy was more frequent in patients who are currently with mania compared to controls (Lippmann et al., 1982; Nasrallah et al., 1981, 1982; Weinberger et al., 1982). One study did not find differences in cerebellar volume between patients with schizophrenia, bipolar disorders, and healthy controls (Yates et al., 1987), whereas another found that cerebellar atrophy was associated with alcohol use history. This finding has not been consistently controlled for in other studies (Lippmann et al., 1982). In our study, alcohol abuse was an exclusion criterion. In a voxel-based MRI study, Adler and colleagues (2007) observed increased volumes in the cerebellum bilaterally in first-episode BD subjects (Adler et al., 2007). In a longitudinal VBM study, patients with BD showed a decrease in cerebellar gray matter density over 4 years, and this decline was more rapid than that observed in healthy control subjects (Moorhead et al., 2007). McDonald and colleagues (2005), however, found no abnormalities in BD patients who had experienced psychotic symptoms compared to controls (McDonald et al., 2005). Our results are in agreement with previous ROI studies. Vermal subregions V2 and V3 were smaller in BD subjects (Monkul et al., 2008), mainly in those with a history of multiple episodes (DelBello et al., 1999; Mills et al., 2005). In contrast to older CT studies (Lippmann et al., 1982; Nasrallah et al., 1981, 1982; Weinberger et al., 1982) and our data, bipolar patients from the former study (Monkul et al., 2008) did not exhibit significantly smaller cerebellar hemispheres compared with healthy subjects. However, these results, as in the present study, suggest that cerebellar vermal atrophy may occur during the course of BD, either as a result of medication exposure or illness progression. Interestingly, Brambilla et al. (2001) found that patients with at least one first-degree relative with a history of mood disorders had smaller cerebellar hemispheres and vermis volumes, and larger left lateral ventricle volumes compared with patients with BD without a first-degree family history of BD (Brambilla et al., 2001). Finally, Arcudi et al. (2000) reported right cerebellar hemisphere and vermis agenesis in autopsy findings in a case of suicide behavior, low IQ, and personality disorder. In a MRI functional study, Jollant et al. (2008) observed reduced activity in the right cerebellum in euthymic men with a history of major depressive disorder and suicidal behavior. Moreover, there is evidence that the cerebellum is involved in
Table 1 Demographic and clinical data. Variables
Controls (n = 22)
Bipolar disorder (n = 40)
Bipolar disorder without history of suicide attempt (n = 20)
Bipolar disorder with history of suicide attempt (n = 20)
χ2/F
p
Femalesa Aged Years of schoolingb N. episodesb
12 (54.54%) 37.72 ± 13.63 11.32 ± 2.81 –
29 (72.50%) 40.91 ± 10.02 11.65 ± 3.52 8.41 ± 6.91
16 (80.00%) 41.9 ± 8.9 11.3 ± 3.8 6.1 ± 3.8
13 (65.00%) 39.94 ± 11.12 11.91 ± 3.16 10.10 ± 8.33
2.01b, 3.05c 1.14e, 0.72f 0.19e, 0.26f 4.61f
0.16b, 0.22c 0.29e, 0.49f 0.66e, 0.77f 0.04f
a b c d e f
Number (percentage). Controls versus bipolar (χ2, p value). Controls versus bipolar with and without suicide history (χ2, p value). Mean ± SD. Controls versus bipolar (t-test, p value). Controls versus bipolar with and without suicide history (F test; p value).
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Table 2 Intracranial, brain and cerebellar volumes (cm3) in control, bipolar without and with suicide attempts groups. Variable
Control (n = 22)
Bipolar disorder (n = 40)
Bipolar disorder without history of suicide attempt (n = 20)
Bipolar disorder with history of suicide attempt (n = 20)
t/F
p
Intracranial volumea Brain volumea Left cerebelluma Right cerebelluma Vermis
1429.70 ± 157.32
1399.37 ± 153.19
1380.91 ± 138.82
1417.82 ± 167.87
0.55b, 0.55c
0.46b, 0.58c
834.24 ± 56.85 44.31 ± 7.51 45.40 ± 7.48 5.62 ± 0.81
820.71 ± 36.78 40.18 ± 6.03 41.15 ± 6.51 4.76 ± 0.66
816.83 ± 35.17 40.85 ± 5.53 41.80 ± 5.29 4.97 ± 0.71
824.59 ± 38.82 39.50 ± 6.57 40.50 ± 7.62 4.56 ± 0.55
1.29b, 0.79c 5.58b, 2.97c 5.43b, 2.86c 20.20b, 12.19c
0.26b, 0.46c 0.02b, 0.06c 0.02b, 0.06c b 0.016c
a b c
Mean ± SD, cubic centimeters (cm3). Controls versus bipolar (t-test, p value). Controls versus bipolar with and without suicide attempts (F test; p value).
impulsive behavior (Moers-Hornikx et al. 2009), which strongly correlates with suicide. However, our results are not in agreement with this previous data. There are several limitations of this study that are worth considering. First, although the overall sample size of BD patients was reasonable for a study using neuroimaging data, the examined bipolar I patients with a history of suicide attempt was rather small. Thus, there was insufficient statistical power to examine psychopathological phenomena in our BD group. Second, although our findings suggest that BD indicates more severe brain structural anomalies, our findings do not necessarily indicate that these findings are exclusive to BD patients. Third, the cross-sectional design precluded the opportunity to examine chronological relationships between suicide attempt and BD. Further, the study was conducted in two urban tertiary hospitals serving a low- or middle-income population; therefore, these results may not be generalizable to other care service settings. However, one of the strengths of our sample is that it consisted of patients with euthymic BD type I which diagnosis were wellcharacterized and without any comorbidities. In conclusion, cerebellar volumes are reduced in patients with BD as compared to healthy controls. Our results are in agreement with the literature and extend the findings, suggesting that there is no relationship between cerebellar volume and suicide attempts. As BD is a multi-state, heterogeneous disease and different MRI analysis techniques have been employed throughout the literature, there are a variety of conflicting results. Future studies should more thoroughly evaluate the role of the cerebellum in mood disorders. Role of funding sources This project has been supported in part by the Mood and Anxiety Disorders Program (CETHA), Salvador-Bahia, Brazil, and by the National Council of Technological and Scientific Development (CNPq), registered as 480918/2007-4. CETHA and CNPq had no further role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication.
Conflict of interest The authors have no financial disclosures or conflicts of interest relevant to the subject of this article to report.
Acknowledgments The authors would like to thank all of the patients who agreed to be included in this study for their cooperation and resilience in completing the assessments. We also thank the professionals at Image Memorial for their technical assistance.
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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Preliminary communication
Is cerebellar volume related to bipolar disorder? L. Baldaçara a, b,⁎, F. Nery-Fernandes c, M. Rocha c, L.C. Quarantini c, G.G.L. Rocha d, J.L. Guimarães c, C. Araújo d, I. Oliveira c, A. Miranda-Scippa c, A. Jackowski b a b c d
Universidade Federal Tocantins, Tocantins, Brazil Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), Universidade Federal de São Paulo, São Paulo, Brazil Centro de Estudos de Transtornos de Humor e Ansiedade (CETHA), Universidade Federal da Bahia, Salvador, Bahia, Brazil Image Memorial, Medicina Diagnóstica, Salvador, BA, Brazil
a r t i c l e
i n f o
Article history: Received 7 June 2011 Accepted 29 June 2011 Available online 23 July 2011 Keywords: Bipolar disorder Cerebellum Magnetic Resonance Imaging Mood disorders Neurobiology
a b s t r a c t Background: Recent data suggest that cerebellum influences emotion modulation in humans. The findings of cerebellar abnormalities in bipolar disorder (BD) are especially intriguing given the link between the cerebellum emotional and behavioral regulation. The purpose of this study was to evaluate cerebellar volume in patients with euthymic BD type I compared to controls. Moreover, we investigated the possible relationship between cerebellar volume and suicidal behavior. Methods: Forty-patients with euthymic BD type I, 20 with and 20 without history of suicide attempt, and 22 healthy controls underwent an MRI scan. The participants were interviewed using the Structured Clinical Interview with the DSM-IV axis I (SCID-I), the Hamilton Depression Rating Scale (HDRS), the Young Mania Rating Scale (YMRS) and the Barratt Impulsiveness Scale (BIS-11). Results: Groups were age, gender and years of schooling-matched. The left cerebellum (p = 0.02), right cerebellum (p = 0.02) and vermis (p b 0.01) were significantly smaller in the BD group; however, there were no volumetric differences between the BD subjects with and without suicidal attempt. There was no correlation between cerebellar measurements and clinical variables. Limitations: The main strength is that our sample consisted of patients with euthymic BD type I without any comorbidities, however, these results cannot establish causality as the crosssectional nature of the study. Conclusions: Our findings suggest that the reduction in cerebellar volumes observed in BD type I might be a trait-related characteristic of this disorder. Additional studies with larger samples and subtypes of this heterogeneous disorder are warranted to determine the possible specificity of this cerebellar finding. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Structural imaging studies suggest that, although patients with BD exhibit relatively healthy-appearing brains overall,
⁎ Corresponding author at: Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), Edifício de Pesquisas II - UNIFESP, Rua Pedro de Toledo, 669 - 3° andar fundos, Vila Clementino - São Paulo, SP, CEP: 04039-032. Tel./fax: +55 11 5539 1468. E-mail address: [email protected] (L. Baldaçara). 0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2011.06.059
cortical and subcortical brain structures may be impaired. Cerebellar abnormalities go either way (i.e., volumes may be larger or smaller) in amygdala volume (Brambilla et al., 2003; Rosso et al., 2007), hippocampus (Aylward et al., 1994; Beyer et al., 2004; Blumberg et al., 2003), basal ganglia (Ahn et al., 2007; Bielau et al., 2005; Hwang et al., 2006), and prefrontal cortex (Najt et al., 2007; Sharma et al., 2003) are the most common findings in BD. However, these results are not consistent between studies. Multiple factors could contribute to the variability in these findings, including gender-related
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differences, volumetric changes related to the use of mood stabilizers, and genetic variation (Womer et al., 2009). Since the 1960s, studies have posited that the cerebellum plays a role in the experience and regulation of emotion (Nashold and Slaughter, 1969; Schutter and van Honk, 2009), and cerebellar findings have also been reported in BD. Cerebellar atrophy (Lippmann et al., 1982; Nasrallah et al., 1981, 1982; Weinberger et al., 1982), cerebellar gray matter reduction (Moorhead et al., 2007), and smaller vermal subregion V2 and V3 are the main findings in patients with BD (DelBello et al., 1999; Mills et al., 2005; Monkul et al., 2008). In this study, we use the region of interest (ROI) MRI approach to evaluate whether cerebellar volume in patients with euthymic BD type I is reduced as compared to healthy controls. In a second analysis, we assess the association between cerebellar volumes and suicidal behavior. 2. Methods 2.1. Participants We screened a total of 48 patients with euthymic BD type I and 25 healthy controls. Eight patients and three controls were excluded due to a history of neurological illness, head trauma, or inability to complete the MRI exam. Additional exclusion criteria included a lifetime history of substance abuse or a current, serious medical problem within the preceding 6 months. The final sample consisted of 40 patients with euthymic BD type I (20 with a history of suicide attempt and 20 without a history of suicide attempt) and 22 healthy controls. Patients were recruited from the Mood and Anxiety Program of the Federal University of Bahia and were interviewed using the Structured Clinical Interview for the DSM-IV axis I (SCID-I) (First et al., 2002), the Hamilton Depression Rating Scale (HDRS) (Hamilton, 1960), the Young Mania Rating Scale (YMRS) (Young et al., 1978), and the Barratt Impulsiveness Scale (BIS-11) (Bayle et al., 2000). The euthymia criterion was scores for both the YMRS and the HDRS under 7 points. Sociodemographical and clinical data were gathered through a questionnaire. Patients were classified as having positive suicidal history if they reported one or more self-injurious acts committed with the intent to die. Healthy controls were recruited from patient's social network. None of the healthy subjects had a current or previous history of Axis I DSM-IV psychiatric disorder or a first-degree relative with an Axis I psychiatric disorder. 2.2. Magnetic Resonance Imaging Imaging data were acquired at the Image Memorial Medicina Diagnóstica-Bahia-Brazil using a 1.5T Symphony Master/Class Siemens. Structural MR images were acquired using a sagittal T1 acquisition series (TR = 1850 ms, TE= 3.45 ms, flip angle = 13°, NEX = 1, matrix size = 256 × 256, FOV = 24 cm, thickness = 1.0 mm) rendering 160 slices. 2.3. Brain volume Brain volume was measured using voxel-based morphometry (VBM) methodology, as implemented via the VBM Toolbox
in SPM5 (dbm.neuro.uni-jena.de/vbm). This methodology has been described previously (Ashburner and Friston, 2005). The sum of all voxel values within the segmented image approximates the total volume within the corresponding partition. Total brain volume was computed from the sum of gray and white matter volumes (Ashburner and Friston, 2005). 2.4. Cerebellar volumes The cerebellar ROI tracing was performed using the Brains 2 semi-automated model and was manually corrected based on previous studies (Luft et al., 1999; Pierson et al., 2002). The cerebellar hemispheres and vermis were manually traced using protocols, which have been described elsewhere (De Bellis and Kuchibhatla, 2006; Luft et al., 1999; Pierson et al., 2002). The cerebellar ROI measurements began at the point that the cerebellum appeared lateral to the pons. The tentorium cerebelli were considered to be the superior limit of the cerebellum, while the base of the cerebellum itself was considered to be the inferior limit. The cisterna magna and transverse sinus were excluded (De Bellis and Kuchibhatla, 2006). The last slice included was the one at which the cerebellum was no longer distinguishable from the transverse sinus or was no longer visible. The vermis measurement started at the slice where the anterior and/or inferior posterior lobes appeared. Measurements were made until the vermis was no longer visible (De Bellis and Kuchibhatla, 2006). 2.5. Reproducibility To evaluate intra-rater reproducibility, same rater repeated the cerebellar measurements twice, at least 1 week apart, for ten randomly selected subjects. Intra-rater reliability was found to be high (ICC N0.96) for all cerebellar and vermal regions. 2.6. Data analysis Data were codified and analyzed using the Statistical Package for Social Sciences (SPSS for Windows, version 15.0). Prior to conducting analyses, measures were examined for normality using the Shapiro–Wilk test. The level of significance was set at p b 0.05 using a two-tailed test. Differences in proportion were compared using the chisquare test. Continuous variables were compared using Student's t-test and the Analysis of Variance (ANOVA). By employing the General Linear Model, analyses of covariance (ANCOVAs) were performed to investigate volume differences in the brain and cerebellar subregions across groups, after which Duncan's post hoc test was performed. The level of significance was set at p b 0.05 using a two-tailed test. 3. Ethical issues Participants who agreed to participate after the explanation of the study signed an informed consent form. The study was fully approved by the Institutional Ethics Committee of Federal University of Bahia (16/2005).
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4. Results There was no age, gender or years of schooling differences among patients with BD and healthy controls. The mean number of suicide attempts was 1.6 ± 0.8. There was no difference between patients with BD who exhibited suicidal behavior and those who did not in terms of age, gender, and years of schooling. For more details, see Table 1. BIS scores were higher in BD subjects with a history of suicide attempts (67.35 ± 14.80) as compared to both those without attempts (58.34 ± 8.64) and control group (58.52 ± 9.05) (p = 0.05). There were no differences in intracranial and brain volumes between the BD group and the healthy controls. The left cerebellum (p = 0.02), right cerebellum (p = 0.02) and vermis (p b 0.01) were smaller in the BD group (Table 2). Vermal volume was smaller in the BD group than the healthy control group (p b 0.01), although it was similar between the BD groups without and with suicide behavior groups. For more details, see Table 2. There was no correlation between vermal and cerebellar hemisphere volumes and BIS, number of suicide attempts, or number of mood episodes (manic, depressive or mixed episodes). 5. Discussion In this study, we examined anatomical abnormalities in the cerebellum of patients with euthymic BD type I compared to healthy controls. The volumes of the cerebellar hemispheres and the vermis were reduced in the BD group. However, there were no differences between BD subjects with and without a history of suicide attempts. The cerebellum is reciprocally connected to limbic structures, including the amygdala, hippocampus, septum, as well as the cerebral cortex, including prefrontal areas (Heath and Harper, 1974; Snider and Maiti, 1976). This feature provides a strong neuroanatomical basis for the involvement of the cerebellum in emotion regulation. As BD is a multi-state heterogeneous syndrome, a variety of neuroimaging findings are observed in the literature (Emsell and McDonald, 2009; Langan and McDonald, 2009; Liu et al., 2010; Mahon et al., 2009; Monkul et al., 2008). Early Computed Tomography (CT) studies have found cerebellar atrophy in patients with BD. The importance of these findings, however, was limited as only qualitative assessments were performed (Lippmann et al., 1982; Nasrallah et al., 1981, 1982;
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Weinberger et al., 1982). While cerebral atrophy was more frequent in patients with schizophrenia, cerebellar atrophy was more frequent in patients who are currently with mania compared to controls (Lippmann et al., 1982; Nasrallah et al., 1981, 1982; Weinberger et al., 1982). One study did not find differences in cerebellar volume between patients with schizophrenia, bipolar disorders, and healthy controls (Yates et al., 1987), whereas another found that cerebellar atrophy was associated with alcohol use history. This finding has not been consistently controlled for in other studies (Lippmann et al., 1982). In our study, alcohol abuse was an exclusion criterion. In a voxel-based MRI study, Adler and colleagues (2007) observed increased volumes in the cerebellum bilaterally in first-episode BD subjects (Adler et al., 2007). In a longitudinal VBM study, patients with BD showed a decrease in cerebellar gray matter density over 4 years, and this decline was more rapid than that observed in healthy control subjects (Moorhead et al., 2007). McDonald and colleagues (2005), however, found no abnormalities in BD patients who had experienced psychotic symptoms compared to controls (McDonald et al., 2005). Our results are in agreement with previous ROI studies. Vermal subregions V2 and V3 were smaller in BD subjects (Monkul et al., 2008), mainly in those with a history of multiple episodes (DelBello et al., 1999; Mills et al., 2005). In contrast to older CT studies (Lippmann et al., 1982; Nasrallah et al., 1981, 1982; Weinberger et al., 1982) and our data, bipolar patients from the former study (Monkul et al., 2008) did not exhibit significantly smaller cerebellar hemispheres compared with healthy subjects. However, these results, as in the present study, suggest that cerebellar vermal atrophy may occur during the course of BD, either as a result of medication exposure or illness progression. Interestingly, Brambilla et al. (2001) found that patients with at least one first-degree relative with a history of mood disorders had smaller cerebellar hemispheres and vermis volumes, and larger left lateral ventricle volumes compared with patients with BD without a first-degree family history of BD (Brambilla et al., 2001). Finally, Arcudi et al. (2000) reported right cerebellar hemisphere and vermis agenesis in autopsy findings in a case of suicide behavior, low IQ, and personality disorder. In a MRI functional study, Jollant et al. (2008) observed reduced activity in the right cerebellum in euthymic men with a history of major depressive disorder and suicidal behavior. Moreover, there is evidence that the cerebellum is involved in
Table 1 Demographic and clinical data. Variables
Controls (n = 22)
Bipolar disorder (n = 40)
Bipolar disorder without history of suicide attempt (n = 20)
Bipolar disorder with history of suicide attempt (n = 20)
χ2/F
p
Femalesa Aged Years of schoolingb N. episodesb
12 (54.54%) 37.72 ± 13.63 11.32 ± 2.81 –
29 (72.50%) 40.91 ± 10.02 11.65 ± 3.52 8.41 ± 6.91
16 (80.00%) 41.9 ± 8.9 11.3 ± 3.8 6.1 ± 3.8
13 (65.00%) 39.94 ± 11.12 11.91 ± 3.16 10.10 ± 8.33
2.01b, 3.05c 1.14e, 0.72f 0.19e, 0.26f 4.61f
0.16b, 0.22c 0.29e, 0.49f 0.66e, 0.77f 0.04f
a b c d e f
Number (percentage). Controls versus bipolar (χ2, p value). Controls versus bipolar with and without suicide history (χ2, p value). Mean ± SD. Controls versus bipolar (t-test, p value). Controls versus bipolar with and without suicide history (F test; p value).
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Table 2 Intracranial, brain and cerebellar volumes (cm3) in control, bipolar without and with suicide attempts groups. Variable
Control (n = 22)
Bipolar disorder (n = 40)
Bipolar disorder without history of suicide attempt (n = 20)
Bipolar disorder with history of suicide attempt (n = 20)
t/F
p
Intracranial volumea Brain volumea Left cerebelluma Right cerebelluma Vermis
1429.70 ± 157.32
1399.37 ± 153.19
1380.91 ± 138.82
1417.82 ± 167.87
0.55b, 0.55c
0.46b, 0.58c
834.24 ± 56.85 44.31 ± 7.51 45.40 ± 7.48 5.62 ± 0.81
820.71 ± 36.78 40.18 ± 6.03 41.15 ± 6.51 4.76 ± 0.66
816.83 ± 35.17 40.85 ± 5.53 41.80 ± 5.29 4.97 ± 0.71
824.59 ± 38.82 39.50 ± 6.57 40.50 ± 7.62 4.56 ± 0.55
1.29b, 0.79c 5.58b, 2.97c 5.43b, 2.86c 20.20b, 12.19c
0.26b, 0.46c 0.02b, 0.06c 0.02b, 0.06c b 0.016c
a b c
Mean ± SD, cubic centimeters (cm3). Controls versus bipolar (t-test, p value). Controls versus bipolar with and without suicide attempts (F test; p value).
impulsive behavior (Moers-Hornikx et al. 2009), which strongly correlates with suicide. However, our results are not in agreement with this previous data. There are several limitations of this study that are worth considering. First, although the overall sample size of BD patients was reasonable for a study using neuroimaging data, the examined bipolar I patients with a history of suicide attempt was rather small. Thus, there was insufficient statistical power to examine psychopathological phenomena in our BD group. Second, although our findings suggest that BD indicates more severe brain structural anomalies, our findings do not necessarily indicate that these findings are exclusive to BD patients. Third, the cross-sectional design precluded the opportunity to examine chronological relationships between suicide attempt and BD. Further, the study was conducted in two urban tertiary hospitals serving a low- or middle-income population; therefore, these results may not be generalizable to other care service settings. However, one of the strengths of our sample is that it consisted of patients with euthymic BD type I which diagnosis were wellcharacterized and without any comorbidities. In conclusion, cerebellar volumes are reduced in patients with BD as compared to healthy controls. Our results are in agreement with the literature and extend the findings, suggesting that there is no relationship between cerebellar volume and suicide attempts. As BD is a multi-state, heterogeneous disease and different MRI analysis techniques have been employed throughout the literature, there are a variety of conflicting results. Future studies should more thoroughly evaluate the role of the cerebellum in mood disorders. Role of funding sources This project has been supported in part by the Mood and Anxiety Disorders Program (CETHA), Salvador-Bahia, Brazil, and by the National Council of Technological and Scientific Development (CNPq), registered as 480918/2007-4. CETHA and CNPq had no further role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication.
Conflict of interest The authors have no financial disclosures or conflicts of interest relevant to the subject of this article to report.
Acknowledgments The authors would like to thank all of the patients who agreed to be included in this study for their cooperation and resilience in completing the assessments. We also thank the professionals at Image Memorial for their technical assistance.
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