JOURNAL OF PSYCHIATRIC RESEARCH

Journal of Psychiatric Research 39 (2005) 347–354

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Anatomical MRI study of corpus callosum in unipolar depression Acioly L.T. Lacerda a,b, Paolo Brambilla a,c,d, Roberto B. Sassi a,e, Mark A. Nicoletti a,c, Alan G. Mallinger a,f, Ellen Frank a,g, David J. Kupfer Matcheri S. Keshavan a, Jair C. Soares c,i,j,*

a,h

,

a

c

Department of Psychiatry, School of Medicine,Western Psychiatric Institute and Clinic, University of Pittsburgh, Pittsburgh, PA, USA b Department of Psychology, University of Greater ABC (UniABC), Santo Andre´, Brazil Division of Mood and Anxiety Disorders, Department of Psychiatry, Health Science Center, University of Texas, MC 7792, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA d Department of Pathology and Experimental and Clinical Medicine, Section of Psychiatry, University of Udine, Udine, Italy e Department of Psychiatry, Institute of Psychiatry, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil f Department of Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA g Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA h Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA i Department of Radiology, Health Science Center, University of Texas, San Antonio, TX, USA j South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, USA Received 26 September 2003; received in revised form 30 September 2004; accepted 5 October 2004

Abstract Previous studies have suggested abnormal cerebral lateralization in major depressive disorder (MDD). Few controlled MRI studies have investigated the corpus callosum (CC), the largest commissura connecting the two cerebral hemispheres, in MDD. This study investigated anatomical abnormalities in the CC and its subdivisions in MDD patients. Twenty-two unmedicated MDD patients and 39 healthy subjects underwent brain magnetic resonance imaging (MRI). Measurements of the CC and its sub-regions were performed with a semi-automated software (NIH Image, version 1.62). ANCOVA with age, gender, and intra-cranial volume (ICV) as covariates showed no significant differences in CC measurements between patients and controls (df = 1,56; p > 0.05). However, patients with familial MDD had a significantly larger middle genu area (F1,45 = 4.252; p = 0.045) compared to healthy controls, and significantly larger middle genu (F1,13 = 5.366; p = 0.037), anterior splenium (F1,13 = 6.27; p = 0.026), and middle splenium areas (F1,13 = 4.706; p = 0.049) compared to patients with non-familial MDD. Although preliminary, our findings suggest that anatomical abnormalities in CC may be restricted to patients with familial MDD, with possible enlargement of CC in this particular sub-group. The possible role of callosal abnormalities in the pathogenesis of mood disorders should be further examined.
2004 Elsevier Ltd. All rights reserved. Keywords: Neuroimaging; Corpus callosum; Mood disorders; Major depressive disorder; Magnetic resonance imaging

1. Introduction Over the past decade, we have witnessed important advances in the elucidation of brain mechanisms in*

Corresponding author. Tel.: +1 210 567 5492; fax: +1 210 567 3759. E-mail address: [email protected] (J.C. Soares).

0022-3956/$ - see front matter
2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2004.10.004

volved in pathophysiology of major depressive disorder (MDD). Neuroimaging studies have increasingly played an important role in these advances. Several studies have demonstrated both anatomical and functional brain abnormalities in this disorder (Guze and Gitlin, 1994; Soares and Mann, 1997a,b; Soares et al., 1996). Such investigations have culminated with the formulation

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of a biological model of depression, which postulates that abnormalities in frontal-limbic-subcortical circuits would play an important role in its pathophysiology (Cummings, 1993a; Davidson et al., 2002; Drevets and Ongur, 1998; Soares and Mann, 1997a,b; Mayberg, 2002; Strakowski et al., 2002). The corpus callosum (commissura maxima) is the largest structure connecting corresponding regions of the cerebral cortex in the two cerebral hemispheres, integrating motor, sensory, and cognitive functions of the brain. More than half of the axons composing the corpus callosum (CC) are myelinated, what confers this structure its remarkable appearance in midsagittal T1weighted MRI images (Egaas et al., 1995; Sperry, 1984). Supported by consistent findings from the classic commissurotomy (Ôsplit-brainÕ) studies, the CC became a focus of interest for psychiatric research in the 1970s. Behavioral deficits observed in those patients permitted researchers to speculate about a potential role of this structure in pathophysiology of psychiatric disorders. In a classic study, Rosenthal and Bigelow (1972) found CC as the only brain structure significantly different in a group of schizophrenic patients compared to healthy controls, indicating a possible inter-hemispheric dysfunction in schizophrenia. A sizable literature suggests a possible involvement of the CC in the pathophysiology of different neuropsychiatric diseases such as attentiondeficit hyperactivity disorder (Hynd et al., 1991), multiple sclerosis (Pozzilli et al., 1991), Down syndrome (Wang et al., 1992), Williams syndrome (Wang et al., 1992), schizophrenia (Mohr et al., 2000), autism (Egaas et al., 1995), and bipolar disorder (Brambilla et al., 2003; Coffman et al., 1990). Accumulated data from neuropsychological, EEG, and neuroimaging studies, as well as studies implicating left-sided brain lesions in depression, have provided support for the hypothesis of abnormal cerebral lateralization in unipolar depression (Knott et al., 2001; Saxena et al., 2001; Vataja et al., 2001). Those findings suggest a possible involvement of abnormalities in inter-hemispheric information transfer in patients suffering from MDD. Hence, the corpus callosum, as the most important structure inter-connecting the cerebral hemispheres, could play a significant role in the pathophysiology of MDD. Neuroimaging (Drevets et al., 1997; Drevets and Ongur, 1998; Nolan et al., 2002) and postmortem (Ongur et al., 1998; Rajkowska et al., 1999) studies have demonstrated that neuroanatomical abnormalities in sub-regions of the prefrontal cortex are most prominent in MDD patients who have a family history of mood disorders among first-degree relatives. Nonetheless, in regard to anatomical abnormalities in sub-genual prefrontal cortex, such abnormalities have not been found consistently in all studies (Brambilla et al., 2002; Bremner et al., 2002). Few controlled MRI studies have investigated the size or

shape of the CC in MDD, although there are different reports that relate depressive syndromes to callosal abnormalities or agenesis (David et al., 1993). Wu et al. (1993), found the anterior and posterior quarters of the CC significantly larger in MDD patients, whereas two subsequent studies (Husain et al., 1991; Parashos et al., 1998) did not find significant differences in CC size in MDD patients compared to controls. Based upon regional differences in its fiber composition and topographic mapping of cortical areas to specific regions, the CC has previously been divided into nine sub-regions (Fig. 1) (Keshavan et al., 2002). The main objective of the present study was to examine possible abnormalities in area, length, and shape of the CC and its sub-divisions in a group of unmedicated depressive patients in comparison to healthy controls. Additionally, we investigated the relationship between callosal measures and clinical variables. Based on previous neuroimaging and neuropsychological studies that found prefrontal and temporal abnormalities in MDD (Biver et al., 1994; Freedman, 1994; George et al., 1993; Goodwin, 1997; Klemm et al., 1996; Liotti and Mayberg, 2001; Soares and Mann, 1997a,b), we hypothesized that patients would have abnormalities in anterior genu (callosal sub-region comprised primarily by fibers inter-connecting prefrontal cortex) and anterior and middle splenium (inter-connecting temporal cortex).

2. Methods 2.1. Subjects Twenty-two MDD patients (mean age ± SD = 41.4 ± 11.1 years, ranging from 18 to 59 years), as determined by the Structured Clinical Interview for DSM IV (SCID-IV) (Spitzer et al., 1994), were enrolled in this study. All subjects were outpatients and were drug-free for at least 14 days preceding the scan. Symptom severity was rated with the Hamilton Depression Rating Scale (HDRS) 17 and 25 items (Hamiltom, 1960). Exclusion criteria were the presence of any comorbid psychiatric disorder, current medical problems, lifetime history of alcohol or substance dependence, as well as alcohol or substance abuse within the six months prior to the scanning. Thirty-nine healthy subjects (mean age ± SD = 35.8 ± 10.5 years, ranging from 21 to 59 years), as determined by the SCID-IV non-patient version (SCID-NP) were recruited. We excluded subjects with any lifetime or current DSM-IV axis I diagnosis, current medical problems, history of psychiatric disorders among firstdegree relatives, and history of neurological disease. All subjects provided written informed consent, after being explained all relevant information related to study participation. This protocol was approved by the University of Pittsburgh IRB.

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Fig. 1. This figure illustrates the corpus callosum and its main divisions (genu, anterior body, isthamus posterior body, and splenium) and subdivision (anterior, middle, and posterior genu and anterior, middle, and posterior splenium).

The information on family history of mood disorders was retrieved by inquiring patients, during the SCID-IV interviews, reviewing medical records, and/or inquiring accompanying relatives. Family history was considered positive if there was at least one first-degree relative who had ever been diagnosed as having unipolar or bipolar disorder by a physician. 2.2. Imaging procedures A 1.5 T GE Signa Imaging System running version Signa 5.4.3 software (General Electric Medical Systems, Milwaukee, WI) was used to acquire a T-1 weighted spin-echo sagittal sequence of 3-mm thick slices (TR = 25 ms, TE = 17 ms, nutation angle = 40, FOV = 24 cm, NEX = 1, matrix size = 256 · 192) to obtain 28 sagittal images covering the entire brain. Before scanning, a sagittal scout series (nine to eleven 5-mmthick slices with a 1-mm interslice gap) was performed to determine image quality and clarity as well as subject head position. Measurements were conducted on an Apple Macintosh Power PC (Mac OS 7.5.5) with the aid of the semi-automated software NIH Image, version 1.62 (National Institute of Health). The CC was manually traced on the mid-sagittal slice by a trained researcher (M.A.N.) blind to study hypotheses, group assignment, and subjectsÕ identity, in reference to standard brain atlases (Jackson and Duncan, 1996; Yuh et al., 1994). Following a computer automated method, the CC was divided into genu, body, isthmus, and splenium using landmarks adapted from

Witelson (Witelson, 1989). Both genu and splenium were further divided into three sub-regions: anterior, middle, and posterior (Fig. 1; Keshavan et al., 2002). Reliability was assessed using intra-class correlation coefficients (ICCs). These coefficients, calculated by having two raters independently tracing 10 training scans, were: 0.99 for total callosal area, 0.99 for callosal length, 0.94 for total genu, 0.96 for anterior body, 0.93 for posterior body, 0.93 for isthmus, 0.97 for total splenium, 0.93 for anterior genu, 0.92 for middle genu, 0.90 for posterior genu, 0.91 for anterior splenium, 0.95 for middle splenium, 0.91 for posterior splenium, 0.99 for splenium circularity. All callosal areas were expressed in cm2, length was expressed in cm, and a number expressed splenium circularity, denoting the splenium circularity compared to a perfect circle, which is considered 1 for circularity. The ICC for Intracranial brain volumes (ICVs) was 0.98. 2.3. Corpus callosum measurements We traced the corpus callosum following its edge in the mid-sagittal slice, where its structure appeared most remarkable. Criteria to identify the correct slice included a distinct outline of the CC and absence of visible intrusion of gray and white matter. A computer macro was used to connect the most anterior with the most posterior pixel of the CC (Fig. 1(a)). This line represented the overall length of the CC. The four main callosal regions (genu, body, isthmus, and splenium) were measured utilizing a computer-generated division of the CC adapted

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from Witelson (1989). A perpendicular bisection of the line connecting the endpoint of the length line within the genu with the mid-point of the line separating the genu from the body further divided the genu into its anterior, middle and posterior portions. The line connecting the endpoint of the length line within the splenium with the midpoint of the line separating the isthmus and the splenium was sectioned by two perpendicular lines, dividing the splenium into its anterior, middle, and posterior sub-regions (Fig. 1).

iable, and age, gender, and ICV as covariates, in order to compare callosal measurements between patients and controls, and between specific patient subgroups. SpearmanÕs correlation coefficients were used to examine the relationship between callosal measures and clinical and demographic variables that did not follow a normal distribution. Finally, ANCOVA was performed to evaluate the effects of gender on anatomical measures.

2.4. Statistical analyses

3. Results

All statistical analyses were conducted using SPSS for Windows software, version 10.0 (SPSS Inc., Chicago, 1999). The analyses were two-tailed and evaluated for significance at the 0.05 alpha level. The callosal measurements were found to be normally distributed according to the Shapiro–Wilks test. The general linear model analysis of covariance (ANCOVA) was performed with diagnostic group as the class var-

As presented in Table 1, no significant differences in callosal measures were found between patients and healthy controls, or between euthymic and acutely depressed patients (ANCOVA; age, gender, and ICV as covariates; df = 1,56; p > .05). However, patients with family history of MDD (N = 11) showed significantly larger middle genu (ANCOVA; age, gender, and ICV as covariates; F1,13 = 5.366; p = .037), anterior

Table 1 Callosal measures Callosal measures 2

Total callosal area (cm ) Callosal length (cm) Total genu area (cm2) Anterior body area (cm2) Posterior body area (cm2) Isthmus area (cm2) Total splenium area (cm2) Anterior genu area (cm2) Middle genu area (cm2) Posterior genu area (cm2) Anterior splenium area (cm2) Middle splenium area (cm2) Posterior splenium area (cm2) Splenium circularity

MDD patients

Healthy controls

F1,56

5.76 ± 0.98 7.36 ± 0.52 2.25 ± 0.40 0.62 ± 0.12 0.55 ± 0.12 0.47 ± 0.13 1.71 ± 0.33 1.14 ± 0.22 0.51 ± 0.11 0.45 ± 0.11 0.44 ± 0.12 0.61 ± 0.12 0.52 ± 0.13 0.72 ± 0.07

5.99 ± 0.95 7.34 ± 0.43 2.25 ± 0.39 0.65 ± 0.13 0.61 ± 0.13 0.52 ± 0.11 1.81 ± 0.32 1.14 ± 0.26 0.52 ± 0.11 0.45 ± 0.10 0.45 ± 0.11 0.63 ± 0.13 0.53 ± 0.17 0.72 ± 0.06

2.68 0.24 0.902 0.15 3.082 2.333 2.261 0.146 0.936 0.641 0.027 0.537 2.303 0.31

Effect size (CohenÕs d) 0.24 0.04 0 0.24 0.47 0.43 0.31 0 0.09 0 0.09 0.16 0.06 0

p 0.607 0.877 0.346 0.904 0.085 0.132 0.138 0.703 0.337 0.427 0.870 0.467 0.135 0.861

Table 2 Callosal measures in familial and non-familial MDD patients Callosal measures 2

Total callosal area (cm ) Callosal length (cm) Total genu area (cm2) Anterior body area (cm2) Posterior body area (cm2) Isthmus area (cm2) Total splenium area (cm2) Anterior genu area (cm2) Middle genu area (cm2) Posterior genu area (cm2) Anterior splenium area (cm2) Middle splenium area (cm2) Posterior splenium area (cm2) Splenium circularity

Familial MDD (N = 11)

Non-familial MDD (N = 7)

F1,13

6.13 ± 0.92 7.38 ± 0.57 2.41 ± 0.39 0.66 ± 0.12 0.59 ± 0.13 0.51 ± 0.12 1.81 ± 0.32 1.20 ± 0.23 0.56 ± 0.11 0.48 ± 0.09 0.51 ± 0.11 0.65 ± 0.13 0.49 ± 0.11 0.72 ± 0.08

5.21 ± 0.98 7.20 ± 0.54 2.06 ± 0.39 0.55 ± 0.13 0.48 ± 0.08 0.41 ± 0.11 1.56 ± 0.36 1.04 ± 0.22 0.47 ± 0.11 0.42 ± 0.15 0.35 ± 0.08 0.52 ± 0.11 0.56 ± 0.16 0.71 ± 0.07

4.163 1.522 4.133 4.175 2.123 1.729 2.882 1.236 5.366 2.319 6.270 4.706 0.238 0.167

Effect size (d) 0.98 0.32 0.9 0.89 0.97 0.86 0.75 0.71 0.82 0.52 1.6 1.06 0.53 0.13

p 0.062 0.239 0.063 0.062 0.169 0.211 0.113 0.286 0.037 0.152 0.026 0.049 0.634 0.689

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Anterior Splenium

Middle genu 0.7

0.8

p= .026**

p= .037* 0.7

0.6

0.6

0.5

0.5

0.4

0.4

0.3

0.2

0.3 Positive Family History

Positive Family History

Negative Family History

Negative Family History

Middle Splenium 0.8

p = .049***

0.7

0.6

0.5

0.4

0.3 Positive Family History

Negative Family History

Fig. 2. This figure illustrates the positive findings for callosal sub-regions in patients with family history of MDD. * ANCOVA, F1,13 = 5.366; ** ANCOVA, F1,13 = 6.270; *** ANCOVA, F1,13 = 4.706.

(F1,13 = 6.270; p = 0.026), and middle splenium (F1,13 = 4.706; p = .049) compared to patients without family history of MDD (N = 7) (Table 2, Fig. 2). Furthermore, patients with familial MDD had larger middle genu areas compared to healthy controls (0.56 ± 0.11 vs. 0.52 ± 0.11; F1,45 = 4.252; p = .045). Four patients were excluded from analyses involving subgroups with and without family history of MDD because it was not possible to determine whether they had or not a first-degree relative with MDD. When the p value was Bonferronicorrected, so that a p value of .0055 (.05/9, number of subregions) was considered significant, all differences were non-significant. All subjects were right-handed as assessed by the Oldfield Handedness Questionnaire (Oldfield, 1971).

Patients were significantly older than controls (mean ± SD age = 41.41 ± 11.12 vs. 35.77 ± 10.55 years; t test; t = 1.967, df = 59, p = .054). There was no significant relationship between age and any callosal measure for the whole subject sample or sub-groups (male or female subjects, healthy controls or patients) (SpearmanÕs correlation coefficient, p > .05), except for circularity, which correlated inversely with age in the total subject sample (r = .287, p = .025) and among female subjects (r = .391, p = .022). Also, patients did not differ from controls with regard to level of education (t test, t = 1.75, df = 59, p = .084) and there was no significant relationship between level of education and callosal measures in patients or controls.

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The patient group (19F/3M) had proportionally more females in comparison with the control group (15F/ 24M) (v2 = 13.082, df = 1, p < .001). We repeated all analyses after excluding male subjects, in order to provide an optimal matching for gender, and results did not change (ANCOVA, age and ICV as covariates; df = 1,30; p > .05). Among patients (N = 22), length of illness (mean ± SD = 11.6 ± 12.2 years) correlated directly with callosal length (r = .584, p = .004) and posterior splenium area (r = .451, p = .035). Age at onset correlated inversely with total callosal area (r = .429, p = .046), callosal length (r = .503, p = .017), and splenium area (r = .426, p = .048).

4. Discussion In the present study, right-handed MDD patients showed no significant differences in callosal measures compared to right-handed healthy subjects. However, patients with familial MDD had a larger middle genu in comparison to both healthy controls and patients with non-familial MDD. In addition, patients with familial MDD showed larger anterior and middle splenium compared to patients with non-familial MDD. To our knowledge, only three previous studies have measured the corpus callosum in patients suffering from unipolar depression and presented conflicting results. Husain et al. (1991) found no statistically significant group differences in measurements of CC and septum pellucidum, although MDD patients had a larger callosal area (p = 0.55; effect size (CohenÕs d) = 0.18) compared to healthy controls. Wu et al. (1993), reported that the anterior (p = 0.002; d = 1.27) and posterior (p = 0.002; d = 1.46) quarters of the CC were significantly larger in MDD patients. This difference was more pronounced in females. Parashos et al. (1998), examining MDD patients and controls, found smaller callosal area in patients (d = .10), not reaching statistical significance. Those inconsistencies in results across studies could be explained at least in part by distinct factors, such as: (1) differences in patient sample characteristics (age, gender, handedness, length of illness, age at onset, and severity); (2) methodological differences in MRI acquisition as well as in callosal measurements; and (3) insufficient statistical power of studies presenting negative findings. The first possibility appears to be pertinent since the only study that presented positive findings (Wu et al., 1993) examined significantly younger patients (mean age = 32.9 years) compared to the other two studies that reported negative findings (Husain et al., 1991; Parashos et al., 1998) (mean age = 53.8 and 55.4 years, respectively). Although using different tracing procedures, all studies, including the present one, showed similar total area means for control groups (ranging from

5.81 to 5.99 cm2). Studies with negative findings (Husain et al., 1991 and Parashos et al., 1998) had small effect sizes, suggesting that the third possibility mentioned above is not the explanation. In contrast, the study that showed increased callosal subregions in MDD (Wu et al., 1993) is the only one with a large effect size. Consistently with the report by Wu et al. (1993), we found significantly increased anterior (middle genu) (d = .82) and posterior (anterior and middle splenium) (d = 1.6 and 1.06, respectively) callosal sub-divisions in patients with familial mood disorders. Additionally, length of illness directly correlated with posterior splenium area, and age at onset directly correlated with total area and splenium. Twin and adoption studies have provided evidence that genetic factors account for at least 50% of the variance in the transmission of mood disorders (Poirier-Littre, 1994). Our findings, which were restricted to the subset of patients with familial MDD, are also consistent with those reported by previous studies that examined the effect of family history of mood disorders in neuroanatomical measurements. As described earlier, a few in vivo neuroimaging studies and postmortem investigations have demonstrated that neuroanatomical abnormalities in prefrontal cortex, especially decreases in gray matter, are most pronounced in patients with familial mood disorders (Bremner et al., 2002; Drevets and Ongur, 1998; Drevets et al., 1997; Nolan et al., 2002). Specific callosal sub-regions topographically relate to different cortical areas, indicating a functional specialization of different sub-regions of the CC. These neuroanatomical findings have been reinforced by studies reporting histological differentiation of callosal segments and clinical observation of patients with partial callosal lesions. Histological studies have suggested that the genu and the anterior and middle splenium are primarily composed by thin (relatively less myelinated) fibers connecting prefrontal areas and temporal and parietal lobes, respectively (Aboitiz et al., 1992a,b). Interestingly, abnormalities in the prefrontal cortex as well as in temporal structures have been consistently described in MDD by both neuroanatomical and neuropsychological studies (Biver et al., 1994; Freedman, 1994; George et al., 1993; Goodwin, 1997; Klemm et al., 1996; Liotti and Mayberg, 2001; Soares and Mann, 1997a,b). George et al. (1993), reviewing available imaging literature in unipolar depression, concluded that ‘‘these data support the view of depression as a disease of the brain in general and of the frontal and temporal lobes in particular’’. The present findings of abnormalities in specific sub-regions of the corpus callosum only in the familial sub-type suggest that, as a group, depressed unipolar patients do not present significant abnormalities in inter-hemisphere connectivity; however, the subtypes with more severe illness, or familial sub-types could possibly present such abnormalities.

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Although the fiber composition of the callosal segments has been well described, the meaning of abnormalities in size of these sub-regions is not clear. Some authors have suggested that an increase in callosal area would be related to a reduction in fiber density due to increases in fiber diameter and/or interfiber distance. On the other hand, some studies suggested that increases in callosal area involve a larger number of fibers, and consequently a better capacity for callosal transfer (Aboitiz et al., 1992a). Impaired callosal transfer could affect the normal process of hemispheric specialization, as described by LaMantia and Rakic (1990). Accumulated data from different sources have suggested that MDD patients have increases in inter-hemispheric asymmetries in brain activity, with the left hemisphere being hypoactive as demonstrated by some neuroimaging studies (Baxter et al., 1989; Gur et al., 1992; Knott et al., 2001; Maeda et al., 2000). On the other hand, patients with unilateral brain lesions are more likely to develop depression if the injuries are located on the left side (Cummings, 1993b). Our findings should be considered preliminary, due to the following limitations. First, our patient and control groups are not optimally matched for gender, which is an important variable affecting callosal size (Steinmetz et al., 1995). However, our results persisted after we excluded male subjects from the analyses, suggesting that our findings are representative of the whole unipolar depressed group. Second, the sample size was a limiting factor in statistical analyses, especially when studying patient sub-groups (e.g., familial versus non-familial). Therefore, our study may not have been properly powered to conclusively exclude any significant differences between sub-groups (familial and non-familial) for the structures where differences have not been found, and those negative findings should be seen with caution. Third, due to the relatively large number of variables compared, the differences involving subgroups with and without family history of MDD did not survive when the p values were Bonferroni-corrected. Last, the family history data were obtained by directly inquiring patients and/ or their relatives, as well as by reviewing patientsÕ charts. Therefore, as first-degree relatives were not systematically assessed with a structured diagnostic interview to conclusively ascertain family history of mood disorders in all relatives, it is possible that some familial cases may have been misclassified as non-familial cases, if those cases went undiagnosed and untreated and did not come to the attention of the patient and/ or family members who provided family history. In conclusion, the present findings suggest that anatomical abnormalities in CC sub-regions may be restricted to patients with familial MDD. It is still unclear what the functional repercussion of callosal enlargement in unipolar depression would be, as well as its possible role in illness pathophysiology. Future

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neuroimaging and neuropsychological studies with larger patient samples are warranted in order to confirm these preliminary findings. Acknowledgements This study was partly supported by Grants MH 01736 and MH 30915 from the National Institute of Mental Health, American Foundation for Suicide Prevention, and CAPES Foundation (Brazil). Dr. Lacerda was funded by the Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (CNPq) – Brazil.

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