Psychiatry Research: Neuroimaging 183 (2010) 119–125

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Psychiatry Research: Neuroimaging

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Corpus callosum abnormalities and potential age effect in men with schizophrenia:An MRI comparative study

Giuseppe Bersania,⁎, Adele Quartinia, Angela Iannitellia, Marco Paolemilia, Flavia Rattia,Claudio Di Biasib, Gianfranco Gualdib

aDepartment of Psychiatric Sciences and Psychological Medicine, “Sapienza” University of Rome, Polo Pontino, “A. Fiorini” Hospital, Terracina (LT), ItalybI Medical Clinic, Magnetic Resonance Imaging Unit, “Sapienza” University of Rome, Italy

⁎ Corresponding author. Tel./fax: +39 6 4454765.E-mail address: giuseppe.bersani@uniroma1.it (G. B

0925-4927/$ – see front matter © 2010 Elsevier Irelanddoi:10.1016/j.pscychresns.2010.04.011

a b s t r a c t

a r t i c l e i n f o

Article history:Received 29 July 2009Received in revised form 8 April 2010Accepted 14 April 2010

Keywords:SchizophreniaWhite matterMotor tasks deficitVisual processing dysfunctionLifetime neuroleptic consumptionWitelson's method

The goal of this investigation was to evaluate corpus callosum (CC) morphometry in schizophrenia. Inconsideration of possible confounders such as age, gender and handedness, our study sample was restrictedto right-handed male subjects, aged 18–55 years. In addition, we controlled for age at onset, illness durationand exposure to antipsychotic medication.Midsagittal CC linear and area Magnetic Resonance Imaging (MRI)measurements were performed on 50 subjects with schizophrenia and 50 healthy controls. After controllingfor midsagittal cortical brain area and age, Analysis of Covariance (ANCOVA) revealed an overall effect ofdiagnosis on CC splenium width and CC anterior midbody area and a diagnosis by age interaction.Independent Student t tests revealed a smaller CC splenium width in the 36- to 45-year-old age group amongthe patients with schizophrenia and a smaller CC anterior midbody area in the 18- to 25-year-old age groupamong the patients with schizophrenia compared with controls. Age, age at onset, illness duration andpsychopathology ratings did not show any significant correlations with the whole CC MRI measurements. Anegative correlation was found between CC rostrum area and the estimated lifetime neurolepticconsumption. The results are discussed in terms of the possibility that CC structural changes may underliethe functional impairments, frequently reported in schizophrenia, of the associated cortical regions.

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1. Introduction

The Corpus callosum (CC), the largest white matter fiber tract in thebrain, provides the majority of axonal transmissions between the twocerebral hemispheres and subserves interhemispheric informationtransfer (Tomasch, 1954). CC maturation spans into adolescence andadulthood (Pujol et al., 1993), and the topographical organization of itsfibers makes it possible to relate abnormalities to specific corticalregions. Callosal fibers connect homotopically positioned cerebral areas.Fibers from the inferior frontal lobes and the anterior and inferiorparietal lobes cross in the genu, and those from the remainingpart of thefrontal area and from the parietal lobe cross in the body of the CC. Fibersfrom the temporal and occipital lobes cross in the splenium (De Lacosteet al., 1985; Pandya andRosene, 1985; Pandya andSeltzer, 1986). TheCChas long been thought to be an important brain structure in theunderstanding of schizophrenia. Its functional significance has beendocumented by studies of interhemispheric transfer of information(Innocenti et al., 2003). In this regard, it has been suggested thatschizophrenia might be associated with impaired interhemispheric

communication (Coger and Serafetinides, 1990). Early post-mortemstudies found an increased thickness of the middle portion of the CC inschizophrenia patients comparedwith controls (Rosenthal andBigelow,1972; Bigelow et al., 1983). Magnetic Resonance Imaging (MRI) studies(Shenton et al., 2001; Bachmann et al., 2003; John et al., 2008) reportedreductions in CC size in schizophrenia, more marked anteriorly(Walterfang et al., 2009), but differences in the rostral and mid-areaof the body containing motor and sensory fibers have also beendescribed (Goghari et al., 2005). RecentMagnetization Transfer Imaging(MTR), MR spectroscopy, and DTI (Diffusion Tensor Imaging) schizo-phrenia studies have reported decreased size in callosal sub-regions,including the genu, body and splenium (Foong et al., 2001; Hulshoff-Polet al., 2004; Rotarska-Jagiela et al., 2008; Kubicki et al., 2008; Ellison-Wright and Bullmore, 2009; Pérez-Iglesias et al., 2010). Keshavan et al.(2002) have documented a smaller CC, anterior genu, anterior body,isthmus, and anterior splenium in first-episode, neuroleptic-naïvepatients, suggesting callosal abnormalities as already present close toillness onset. Cross-sectional comparison of first-episode with chronicschizophrenia patients has highlighted mostly genual abnormalities infirst-episode schizophrenic patients and a more widespread reduction(also involving the isthmus), in the chronic schizophrenia group, thussuggestingposterior callosal involvementwith longerdurationof illness(Walterfang et al., 2008). A longitudinal MRI study of patients with

120 G. Bersani et al. / Psychiatry Research: Neuroimaging 183 (2010) 119–125

schizophrenia (Keller et al., 2003) has suggested that a failure of normalcallosal growth may result in area reductions, particularly in thesplenium, by early adulthood. A subsequent longitudinal DTI andstructural MRI study has reported differences in callosal size betweenschizophrenia patients and healthy control subjects, already present atbaseline, continuing to widen in the chronic phase of the illness(Mitelman et al., 2009).

Sex differences in CC size have been reported (De Lacoste-Utamsing and Holloway, 1982; Witelson, 1989; Sullivan et al., 2001).Post-mortem and MRI studies have concluded that left-handers havelarger CC area than right-handers (Witelson, 1989; Driesen and Raz,1995). Age is known to potentially influence CC size, although thiseffect is mostly evident early in life and associated with myelination(McLaughlin et al., 2007) and later in life with loss of white mattervolume (Sullivan et al., 2006; Ota et al., 2006; Bastin et al., 2008).Lastly, antipsychotic medication has been shown to produce increasesand decreases in regionalwhitematter volume (Bartzokis et al., 2007).

Concerning CC regional analysis, a wide range ofmethods have beenimplemented to subdivide the CC, thereby complicating the picture ofdifferent regional findings. Witelson (1989) devised an approach todefine CC sub-regions according to their anatomical connectivity. Thesame methodology has been used in a studies of a variety of mentaldisorders assessing the CC (Duara et al., 1991; Piven et al., 1997; Lyoo etal., 2002; Von Plessen et al., 2002). To our knowledge, four other studieshave adapted the aforesaid methodology and applied it to a schizo-phrenia population (Jacobsen et al., 1997; Keshavan et al., 2002; Kelleret al., 2003; Goghari et al., 2005).

With this background, we performed a study that was restricted toright-handed male subjects, aged 18–55 years, and controlled for age,age at onset, illness duration and exposure to antipsychotic medication.For regional analysis, in order to use the samemethodologyas thatof theaforementioned CC studies, the Witelson method was adopted.

We hypothesized that CC size in whole brain or at the level ofindividual sub-regions would be reduced in patients with schizo-phrenia compared with controls. We also hypothesized that age-related callosal changes would be different among diagnostic groups,possibly showing a greater decrease in CC size in schizophreniapatients compared with controls amongst older subjects.

2. Materials and methods

2.1. Subjects

Fifty right-handed male patients with schizophrenia from theDepartment of Psychiatric Sciences and Psychological Medicine,“Sapienza” University of Rome, underwent MRI. Psychiatric diagnoseswere determined according to DSM-IV criteria. Demographic infor-mation and past and current symptom history of all patients wereobtained in semi-structured interviews (Table 1). Clinical status wasassessed using the Scale for the Assessment of Negative Symptoms(SANS) (Andreasen, 1983) and the Scale for the Assessment of Positive

Table 1Socio-demographic and clinical characteristics of the study sample.

Socio-demographic andclinical characteristics

Subjects (N=100)

Schizophrenia Control

n=50 n=50

Gender M MHandedness Right RightAge (years) 31.54 (S.D.=10.48) 32.88 (S.D.=10.88)Onset (years) 22.28 (S.D.=7.23) n/aIllness duration (years) 9.23 (S.D.=8.39) n/aTotal lifetimeneuroleptic exposure

3945.37 (S.D.=4172.54) n/a

SANS total score 62.44 (S.D.=22.61) n/aSAPS total score 43.56 (S.D.=18.57) n/a

Symptoms (SAPS) (Andreasen, 1984). For comparison, 50 healthyright-handed male volunteers, screened for major psychiatric ill-nesses, underwent the same procedure. Age was not significantlydifferent between the groups (t=−0.627; df=98; P=0.532).Exclusion criteria for all participants of the study included thefollowing: alcohol or drug abuse (past or present), dementia, epilepsy,Parkinson's disease or other chronic neurological illness, neurosur-gery, mental retardation, tumours, or any other conditions unsuitablefor MRI. Both patients and control subjects gave their informedconsent. At the time of the investigation, 43 of the 50 schizophreniapatients were receiving neuroleptic medication (typical neurolep-tics=22 and atypical neuroleptics=21). An approximate estimate oftotal lifetime neuroleptic consumption in chlorpromazine equivalentunits was calculated by multiplying duration of illness by thechlorpromazine equivalent units of current daily neuroleptic dose(Bazire, 2009; Tamagaki et al., 2005).

2.2. MRI procedures

A 1T Philips Gyroscan scanner (MR Systems Gyroscan NT, soft-ware release 12.1.1.1.) was used to obtain a set of T-1 weighted sagit-tal scout images (2D spin echo, TR=539 ms, TE=15 ms, FOV=230/1.0 mm, 20 slices, THK=5.0/0.5, NSA=2, matrix=205/256, scantime=3:43 m). The full sagittal series was reviewed and on theconsensus of two raters (CDB and GG) a slice was selected based onstringent internal midsagittal landmark criteria (best visualization ofthe CC, the septum pellucidum, the cerebellum and the aqueduct)(Woodruff et al., 1993).

Measurements were performed with Scion Image 4.0.3.2 (ScionCorporation, http://www.scioncorp.com) which is the Windows©version of the NIH Image software. This software provides valid andreliable measurements of specific structures using a semi-automatedsegmentation approach (Keshavan et al., 1995). The steps formeasuring the CC using the Scion Image software have previouslybeen described (Takeda et al., 2003; Venkatasubramaian et al., 2007).First, the CC in the midsagittal section was segmented automaticallyand the total CC area (CCA)wasmeasured. In a second step, a rectanglewas placed over the CC. The lower side of the rectangle cut the twolowest points of the anterior and the posterior parts of the CCtangentially. The rectangle length was determined by two linesperpendicular to this lower side which cut the most anterior (ACC)and themost posterior (PCC)points of the CC. To correct for differencesin spatial orientation of the CC, the outline of each CCwas rotated untilthe ACC-PCC line became horizontal (Witelson, 1989; Jacobsen et al.,1997). The anterior to posterior length and themaximumheight of theCCweremeasured and abbreviated as CCL and CCH. A straight linewasalso drawn to connect the most anterior pixel with the most posteriorpixel of the CC through the point of maximum curvature of the innerborder of the genu. The width of the middle portion, which wasconsidered thewidth of the body of the CC (CCB), wasmeasured alonga line vertical to the former to divide the CC into twoparts. Thewidth ofthe rostrum (CCR) and that of the splenium (CCS) were measuredalong the first horizontal line (Fig. 1). In a third step, fourperpendicular lines were automatically drawn on the CC. Finally, thefifth perpendicular line was drawn at the point where the straight linecuts the inner body of the genu of the CC. Thesefive perpendicular linesdivided the CC, as per Witelson's validated neuroanatomical basis(Witelson, 1989), into halves, thirds and the posterior fifth, with thefollowing regions: A1 (rostrum), A2 (genu), A3 (rostral body), A4(anterior midbody), A5 (posterior midbody), A6 (isthmus), and A7(splenium) (Fig. 2). Overall brain size was controlled for by indexingthe midsagittal cortical brain area (MCBA) as has been done inprevious MRI studies (Rumsey et al., 1996; Keshavan et al., 2002; VonPlessen et al., 2002). The MCBA was delimited by tracing the superiorborder of the CC from the genu to the splenium and then following thecerebrumposteriorly along the inferior border of the occipital lobe and

Fig. 1. Corpus callosum linear measurements. Abbreviations. CCL: CC Length; CCR: CCRostrum width; CCS: CC Splenium width; CCB; CC Body width; CCH: CC Height.

Table 2Mean±S.D. of CC linear measurements (cm) of schizophrenia patients in comparisonwith healthy control subjects.

Schizophrenia Control ANCOVAs

(N=50) (N=50) F Significance

CCL 7.36(0.47) 7.52(0.50) 1.500 0.224CCR 1.14(0.20) 1.16(0.18) 0.194 0.661CCS 1.11(0.17) 1.24(0.20) 11.173 0.001*CCB 0.60(0.08) 0.62(0.10) 0.775 0.381CCH 2.72(0.34) 2.61(0.30) 3.444 0.067

MCBA (Mean±S.D.): schizophrenia—96.28±9.28 cm2; control—98.60±9.01 cm2.Abbreviations. CCL: CC length; CCR: CC rostrum width; CCS: CC splenium width; CCB;CC body width; CCH: CC height; MCBA: midsagittal cortical brain area.

Table 3

121G. Bersani et al. / Psychiatry Research: Neuroimaging 183 (2010) 119–125

continuing anteriorly over the convexity of the brain. Finally, wetraced posteriorly along the inferior border of the frontal lobe until thegenu of the CC was reached again.

2.3. Statistical analysis

Statistical analysis was performed using the SPSS software package(Version 16.0; SPSS Inc., Chicago).

Exploratory data analysis revealed normally distributed mor-phometric measurements in both groups, without any outliers.Clinical and demographic variables also satisfied the criteria for anormal distribution. The ages of the two groups were comparedusing the independent Student t test. To assess inter-rater reliability(interclass r), two raters (AQ andMP), after being trained initially byan experienced neuroradiologist (CDB), rated 50 coded images(schizophrenia patients=25; healthy control subjects=25) indepen-dently (r=0.91–1.00). To assess intra-rater reliability (AQ) (intra-classr), 50 coded images (schizophrenia patients=25; healthy controlsubjects=25) were analysed on two separate occasions, 2 to 4 weeksapart (r=0.99–1.00). Whole CC area and CC length were comparedbetween schizophrenia patients and healthy control subjects by GLMUnivariate ANCOVA with diagnosis as fixed factor and age andMCBA as covariates. CC linear sub-measurements and areas of eachsubdivision were compared separately between the two groups byGLM Multivariate ANCOVA (MANCOVA) with diagnosis as fixedfactor and age and MCBA as covariates. Diagnosis by age interactionwas also investigated. Schizophrenia patients and healthy controlsubjects were then stratified by age groups (18–25, 26–35, 36–45,and 46–55), using one-way Analysis of Variance (ANOVA) withFisher LSD (Least Sig. Difference) post hoc test and independentStudent t test, to evaluate differences in the CC linear and areameasurements by age groups plus, according to age group, bydiagnostic groups. Significant findings were followed up with GLMANCOVA to adjust for MCBA. Before conducting parametric compar-ison, homogeneity of variance was checked, using the Levene test,eventually, with a log10 transformation of the variables to equalizethe variance. For ANCOVA, the assumption of homogeneity of

Fig. 2. Corpus callosum area subdivisions as per Witelson's method. Abbreviations.CCA1: CC rostrum area; CCA2: CC genu area; CCA3: CC rostral body area; CCA4: CCanterior midbody area; CCA5: CC posterior midbody area; CCA6: CC isthmus area;CCA7: CC splenium area.

regression slopes was not violated. Partial correlation analysisbetween age and CC morphometric data was carried out withMCBA as covariate. Partial correlation analyses between age at onset,illness duration, psychopathology ratings, estimated lifetime neuro-leptic consumption and CC morphometric data were carried outwith age and MCBA as covariates. To further evaluate the effect ofantipsychotics on CC size, an additional one-way ANOVA was per-formed with CC linear and area MRI measurements entered asdependent measures and antipsychotic treatment group (typicalsand atypicals) entered as the main effect. Because of the number oftests performed, a conservative alpha level of 0.01 was used.

3. Results

3.1. CC morphometric data analysis

No significant difference was found in themeasure of the whole CCarea between schizophrenia patients and healthy control subjects(Table 3). CC length did not differ significantly between the groups(Table 2), bit there was a significant effect of MCBA (F=7.515,P=0.007). GLM MANCOVA of the CC linear sub-measurementsrevealed significant group differences (Hotelling's Trace, F=10.746,Pb0.0001). There was a significant diagnosis by age interaction(Hotelling's Trace, F=5.103, Pb0.0001), while there was no signif-icant effect of age (Hotelling's Trace, F=0.854, PN0.01) or MCBA(Hotelling's Trace, F=2.638, PN0.01). Similarly, GLM MANCOVA ofthe seven CC area subdivisions revealed significant group differences(Hotelling's Trace, F=4.824, Pb0.0001). There was a significantdiagnosis by age interaction (Hotelling's Trace, F=2.205, P=0.009),while there was no significant effect of age (Hotelling's Trace,F=0.782, PN0.01) or MCBA (Hotelling's Trace, F=0.997, PN0.01).Individual ANCOVAs, revealed significantly smaller CC spleniumwidth and CC anterior midbody area in patients with schizophreniacompared with controls (Tables 2 and 3) (covarying only by age did

Mean±S.D. of CC area measurements (cm2) of schizophrenia patients in comparisonwith healthy control subjects.

Schizophrenia Control ANCOVAs

(N=50) (N=50) F Significance

CCA 6.95(1.06) 7.29(1.27) 1.701 0.195CCA1 0.32(0.12) 0.28(0.11) 2.617 0.109CCA2 1.57(0.36) 1.60(0.35) 0.056 0.813CCA3 0.89(0.16) 0.92(0.17) 0.281 0.597CCA4 0.73(0.10) 0.84(0.16) 13.336 0.000*CCA5 0.73(0.14) 0.77(0.16) 0.888 0.348CCA6 0.62(0.15) 0.65(0.17) 1.222 0.272CCA7 2.01(0.33) 2.09(0.39) 1.002 0.319

MCBA (Mean±S.D.): schizophrenia—96.28±9.28 cm2; control—98.60±9.01 cm2.Abbreviations. CCA: CC total area; CCA1: CC rostrum area; CCA2: CC genu area; CCA3:CC rostral body area; CCA4: CC anterior midbody area; CCA5: CC posterior midbodyarea; CCA6: CC isthmus area; CCA7: CC splenium area; MCBA: Midsagittal Cortical BrainArea.

Table 4CC Mean±S.D. of CC linear measurements (cm) of schizophrenia patients in comparison with healthy control subjects according to age groups.

Ages 18–25 P Ages 26–35 P Ages 36–45 P Ages 46–55 P

Patients=18 Patients=16 Patients=11 Patients=5

Controls=13 Controls=18 Controls=11 Controls=7

CCL: Schizophrenia 7.25(0.41) 0.338 7.36(0.50) 0.107 7.42(0.54) 0.752 7.64(0.46) 0.471Control 7.39(0.43) 7.66(0.55) 7.49(0.51) 7.43(0.47)CCR: Schizophrenia 1.13(0.22) 0.961 1.17(0.21) 0.767 1.10(0.11) 0.146 1.17(0.33) 0.446Control 1.13(0.17) 1.19(0.19) 1.20(0.19) 1.06(0.14)CCS: Schizophrenia 1.13(0.13) 0.348 1.13(0.22) 0.182 1.09(0.14) 0.006* 1.08(0.25) 0.296Control 1.17(0.16) 1.22(0.15) 1.39(0.28) 1.21(0.16)CCB: Schizophrenia 0.60(0.07) 0.759 0.63(0.09) 0.746 0.59(0.08) 0.721 0.56(0.13) 0.550Control 0.61(0.07) 0.64(0.13) 0.60(0.10) 0.61(0.11)CCH: Schizophrenia 2.67(0.32) 0.767 2.78(0.28) 0.297 2.74(0.42) 0.123 2.61(0.48) 0.809Control 2.64(0.32) 2.67(0.33) 2.79(0.22) 2.56(0.29)

Abbreviations. CCL: CC Length; CCR: CC Rostrum width; CCS: CC Splenium width; CCB; CC Body width; CCH: CC Height.

122 G. Bersani et al. / Psychiatry Research: Neuroimaging 183 (2010) 119–125

not change the result)[CC splenium width: F(1,97)=10.991,P=0.001; CC anterior midbody area: F(1,97)=15.896, Pb0.001],and a diagnosis by age interaction [CC splenium width: F(2,96)=5.932, P=0.004; CC anterior midbody area: F(2,96)=5.662,P=0.005]. No significant age or MCBA effect was found for all CClinear sub-measurements and area of each subdivision (PN0.01).

3.2. Age effect analysis

Partial correlation analysis did not show significant correlationbetween age and any of the different CC linear and area measure-ments (PN0.01). Comparing overall CC linear and area measure-ments by age groups, one-way ANOVA, done separately inschizophrenia patients and controls, did not reveal significantdifferences (PN0.01). Comparing overall CC linear and area mea-surements by diagnostic groups according to age groups, indepen-dent Student t test revealed a significantly smaller CC spleniumwidth in the schizophrenia subgroup aged 36–45 years comparedwith controls (Table 4). In the schizophrenia subgroup aged 18–25,a significantly smaller CC anterior midbody area was alsodemonstrated (Table 5). After adjusting for MCBA, GLM ANCOVAsconfirmed the results [CC splenium width: F(1,19)=9.025,P=0.007; CC anterior midbody area: F(1,29)=7.962, P=0.009)].No significant differences were found for the other CC linear andarea measurements between diagnostic groups according to agegroups (PN0.01).

Table 5CC Mean±S.D. of CC area measurements (cm2) of schizophrenia patients in comparison w

Ages 18–25 P Ages 26–35

Patients=18 Patients=16

Controls=14 Controls=18

CCA: Schizophrenia 6.71(0.66) 0.119 7.33(1.38)Control 7.20(0.99) 7.54(1.42)CCA1: Schizophrenia 0.32(0.11) 0.718 0.34(0.17)Control 0.30(0.12) 0.27(0.12)CCA2: Schizophrenia 1.49(0.22) 0.668 1.76(0.46)Control 1.53(0.31) 1.69(0.39)CCA3: Schizophrenia 0.89(0.13) 0.459 0.89(0.13)Control 0.92(0.13) 0.93(0.20)CCA4: Schizophrenia 0.71(0.07) 0.006* 0.76(0.11)Control 0.82(0.13) 0.88(0.19)CCA5: Schizophrenia 0.70(0.08) 0.144 0.79(0.14)Control 0.74(0.07) 0.80(0.19)CCA6: Schizophrenia 0.60(0.08) 0.174 0.65(0.13)Control 0.65(0.11) 0.67(0.17)CCA7: Schizophrenia 1.95(0.27) 0.240 2.03(0.39)Control 2.08(0,.4) 2.10(0.39)

Abbreviations. CCA: CC Area; CCA1: CC rostrum area; CCA2: CC genu area; CCA3: CC rostral bisthmus area; CCA7: CC splenium area.

3.3. Exploratory analysis of CC morphometric data, clinical parametersand antipsychotic medication

No correlationwas found between SANS and SAPS total and subtotalscores and any of the CC linear and areameasurements (PN0.01). Age atonset and duration of illness also did not show significant correlationswith the different CC morphometric data (PN0.01). There was asignificant negative correlation between CC rostrum area and theestimated lifetime neuroleptic consumption, both before (r=−0.406,P=0.007) and after controlling for age and MCBA (r=−0.399,P=0.010). No other significant correlations were found between thedifferent CC morphometric data and the estimated lifetime neurolepticconsumption (PN0.01). Among the two antipsychotic treatment groups(typicals and atypicals), one-way ANOVA did not reveal significantdifferences in any of the CC linear and area measurements (PN0.01).

4. Discussion

The present study found a smaller CC splenium width in patientswith schizophrenia compared with control subjects. To our knowledge,this is the first MRI study to report size differences in the CC spleniumwidth in schizophrenia. Nonetheless, Downhill et al. (2000), Keshavanet al. (2002) andKeller et al. (2003)have reported a smallerCCspleniumarea in patients suffering with schizophrenia compared with controls.Considerable data from monkeys and humans suggest that occipital,parietal and temporal lobe fibers generally transverse through the

ith healthy control subjects according to age groups.

P Ages 36–45 P Ages 46–55 P

Patients=11 Patients=5

Controls=11 Controls=7

0.656 6.95(1.02) 0.535 6.61(1.15) 0.7367.27(1.30) 6.88(1.45)

0.203 0.29(0.09) 0.968 0.31(0.05) 0.1900.28(0.09) 0.24(0.11)

0.635 1.46(0.23) 0.096 1.54(0.53) 0.7521.65(0.27) 1.45(0.39)

0.561 0.96(0.17) 0.278 0.78(0.27) 0.2110.87(0.16) 0.96(0.18)

0.045 0.75(0.08) 0.269 0.66(0.18) 0.1300.81(0.16) 0.82(0.14)

0.884 0.72(0.13) 0.507 0.70(0.25) 0.8820.77(0.18) 0.71(0.19)

0.686 0.64(0.20) 0.635 0.50(0.24) 0.7180.68(0.18) 0.55(0.22)

0.261 2.08(0.31) 0.312 1.97(0.47) 0.9352.02(0.47) 1.99(0.39)

ody area; CCA4: CC anterior midbody area; CCA5: CC posterior midbody area; CCA6: CC

123G. Bersani et al. / Psychiatry Research: Neuroimaging 183 (2010) 119–125

splenium (Pandya and Seltzer, 1986;Witelson, 1989; Hofer and Frahm,2006; Park et al., 2008). Specifically, Dougherty et al. (2005) haverevealed dorsal visual areas (dorsal V3, V3A, V3B, and V7) that sendprojections passing through a large band in the middle of the splenium,whereas ventral visual area projections (ventral V3 and V4) passthrough the inferior corner of the splenium. V3 represents an importantsite for the coordinated activity and integration of both the occipitopar-ietal pathway (or dorsal visual-processing stream), important for theperception of visual motion, visuospatial analysis, oculomotor behav-iour and direction of visual attention, and theoccipitotemporal pathway(or ventral visual-processing stream), important for detailed analysis ofthe form and colour of the objects (Gegenfurtner et al., 1997). It receivesinputs from both pathways and has prominent projections to bothmiddle temporal (MT) (strong selectivity for visual motion anddirection) and V4 (principally a colour computation centre)(Grill-Spector and Malach, 2004). Behavioural and electrophysiologicalstudies have highlighted deficiencies in patients with schizophrenia intheir discrimination of motion, trajectory, or location cues, suggesting arelatively specific deficit in the dorsal visual-processing stream (Butleret al., 2005). The demonstration of impaired visual object recognition inschizophrenia patients compared with control subjects has suggested adeficiency in the ventral visual-processing stream as well (Tek et al.,2002; Doniger et al., 2002). Functional imaging studies have reportedchanges in the primary visual cortex activity in patients withschizophrenia (Desco et al., 2003). DTI studies have demonstrated areduced visual white matter in schizophrenia patients compared withcontrols (Butler et al., 2006). Agartz et al. (2001) have additionallyrevealed a reduced fractional anisotropy in the splenium of the CC andadjacent occipital white matter (forceps major) in schizophrenia,without volume loss. Such observations are consistent with our ownfinding of a decreased size of the CC splenium, which connects theoccipital lobes, in schizophrenia. CC splenium also connects the parietaland temporal lobes. In this respect, functional MRI studies in patientswith schizophrenia have shown pronounced impairments in parietaland temporal lobe functioning as assessed by neuropsychological tests,including phonological storage, spatial working memory and episodic/relational memory tasks, respectively (Tek et al., 2002; Barch andCsernansky, 2007; Reichenberg and Harvey, 2007). Quantitative MRIstudies have found reductions in the volume of the parietal andtemporal regions in schizophrenia patients compared with controls(Shenton et al., 2001). Ardekani et al. (2003) have also demonstrated areduction in the white matter integrity for patients with schizophreniain the splenium of the CC plus the left superior temporal gyrus, theparahippocampal gyri, the middle temporal gyri, the inferior parietalgyri, the medial occipital lobe, and the deep frontal perigenual region.

Regarding CC area subdivisions, we have found that schizophreniawas associated with a smaller CC anterior midbody area, primarily withmotor cortical projections. In support of our finding, a study of first-episode, drug-naïve schizophrenia, schizophreniform, and schizoaffec-tive patients reported a significantly smaller anterior body subregion ofthe CC, which is similar to our anterior midbody subdivision (Keshavanet al., 2002). Also in accord with our finding, Goghari et al. (2005)reported smaller rostral body and anterior midbody sub-regions inschizophrenia patients compared with controls. Several studies haveinvestigated functional impairment in motor conduction in schizophre-nia. Single-photon emission computerized tomography has demon-strated activation patterns to be different in patientswith schizophreniaduring a motor task (Günther et al., 1991; Rogowska et al., 2004).Further investigations have found differences in transcallosal inhibitionin schizophrenia (Boroojerdi et al., 1999; Höppner et al., 2001;Daskalakis et al., 2002). Cortical volume reductions regarding the areaof the primary motor cortex have been reported as well (Zhou et al.,2005).

In linewith previous studies, neither total CC size nor linear and areasub-measurements were significantly correlated with age in eithergroup (Woodruff et al., 1997; Meisenzahl et al., 1999; Arnone et al.,

2008; Walterfang et al., 2008). Moreover, our study failed todemonstrate any significant difference amongst age groups in bothschizophrenia and healthy control subjects. A DTI developmentalexamination of the CC across the life span revealed fractional anisotropyvalues that increased in childhood and adolescence, reaching their peakin young adulthood, followed by a non-significant decline in the elderly.Volumetric analysis of CC regions revealed a similar pattern, althoughthis study was restricted to healthy subjects (McLaughlin et al., 2007).We found a differential age relationship in schizophrenia patientscompared with control subjects that was especially pronounced in theCC splenium width and in the CC anterior midbody area. IndependentStudent t test additionally revealed a significant smaller CC spleniumwidth in the schizophrenia subgroup aged 36–45 years compared withcontrols. A significantly smaller CC anterior midbody area, in theschizophrenia subgroup aged 18–25 years was also demonstrated.Concerning CC splenium width, in support of our finding twolongitudinalMRI andDTI schizophrenia studies have provided evidencefor a progressive, possibly neurodegenerative process affecting theposterior CC (Keller et al., 2003; Mitelman et al., 2009). Probably, thenegative finding of a significantly smaller CC splenium width inschizophrenia patients compared with control subjects, in our 46–55age group, could be explained by the loss of statistical power as therewas a reduction in the number of people in the groups. As far as the CCanteriormidbody area is concerned, developmental studies show size ofthe CC increasing until the late twenties (Keshavan et al., 2002), roughlythe time period when most of the patients develop schizophrenia. Thisincrease in size is thought to be related to an increase in axonal size ordue to continued myelination, long after other areas of the brain havematured. Thus, our finding of a significantly smaller CC anteriormidbody area in patients with schizophrenia compared with controlsubjects in the 18–25 age group, also with a trend toward statisticalsignificance (P=0.045) in the 26–35 age group, may be due to areducedmyelination thatwould normally be expected to occur throughchildhood, a sort of developmental breakdown process at a particularpoint of maturation (Kubicki et al., 2008). Although not statisticallysignificant, a smaller CC anterior midbody area has also been found inthe 36–45 and 46–55 age schizophrenia groups in schizophreniapatients compared with controls.

In line with previous studies, we found no relationship of CCmeasurements with age at onset (Foong et al., 2000), illness duration(Meisenzahl et al., 1999; Foong et al., 2000; Rotarska-Jagiela et al., 2008)and SANS and SAPS total and subtotal scores (Goghari et al., 2005;Meisenzahl et al., 1999; Panizzon et al., 2003). Also we did not find asignificant correlation of CC size with antipsychotic medication, exceptfor the CC rostrum area which correlated negatively with lifetimeneuroleptic exposure, likewise confirming previous fractional anisotropyCC research (Rotarska-Jagiela et al., 2008). Interestingly, regardless of theduration of illness, a trend toward a negative correlationwas also shownbetween CC rostrum area and the antipsychotic medication dosage(P=0.047), thus suggesting an association between this particular CCarea and treatment resistance. Antipsychoticmedicationhas been shownto produce increases and decreases in regionalwhitematter,mostlywithatypical antipsychotics increasing and typical antipsychotics decreasingwhite matter volume (Bartzokis et al., 2007). In our study sample nosignificant differencewas found in any of the CCmeasurements betweenthe two antipsychotic treatment groups (PN0.05).

The present study has certain limitations. Although all care wastaken to normalize for average differences in brain size, in this caseusing MCBA as covariate, the superiority of the stereotaxic method,with its linear rescaling of volumes, has clearly been demonstrated(Bermudez and Zatorre, 2001). A further limiting factor was use ofconventional MRI as opposed to DTI analysis. DTI analysis is a morereliable method, and may be more sensitive to differences in CCmorphology. This could explain our lack of a significant difference inthe CC genu between schizophrenia patients and healthy controlsubjects, as reported by the majority of studies. Despite the strengths,

124 G. Bersani et al. / Psychiatry Research: Neuroimaging 183 (2010) 119–125

including a large sample of patients, a neuroanatomically validmethod for analyzing CC, analysis on coded midsagittal images, highinter- and intra-rater reliability, and investigation of the effects of anumber of additional variables such as age at onset, illness duration,antipsychotic medications, and psychopathological ratings.

These findings add to the mounting evidence that CC abnormal-ities are present in schizophrenia. The potential effect of age on CCmorphological abnormalities among schizophrenic patients has alsobeen suggested. Regional analysis of the CC in association withfunctional MRI studies of occipital, parietal, temporal and motor brainareas or transcallosal information transfer in schizophrenia mightprove to be informative.

Acknowledgements

We thank MRI technicians Stefano Caprasecca, Dino D'Amico andLuigi Della Volpe for their help with MRI scan procurement andanalysis.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.pscychresns.2010.04.011.

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