Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 510 – 516 www.elsevier.com/locate/pnpbp

Morphology of the orbitofrontal cortex in first-episode schizophrenia: Relationship with negative symptomatology Acioly L.T. Lacerda a,b , Antonio Y. Hardan c , Ozgur Yorbik d , Madhuri Vemulapalli c , Konasale M. Prasad c , Matcheri S. Keshavan c,e,⁎ a

Interdisciplinary Lab of Neuroimaging and Cognition (LiNC), Department of Psychiatry, Federal University of Sao Paulo, Sao Paulo, Brazil b Neuropsychiatric Division, SINAPSE Institute, Campinas, Brazil c Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA d GATA Child and Adolescent Psychiatry Department, Etlik, Ankara, Turkey e Department of Psychiatry and Behavioral Sciences, Wayne State School of Medicine, Detroit, Michigan, USA Received 13 June 2006; received in revised form 19 October 2006; accepted 30 November 2006 Available online 18 January 2007

Abstract Different studies have documented OFC abnormalities in schizophrenia, but it is unclear if they are present at disease onset or are a consequence of disease process and/or drug exposure. The evaluation of first-episode, drug-naïve subjects allows us to clarify this issue. Magnetic resonance imaging was performed on 43 first-episode, antipsychotic-naïve schizophrenia patients and 53 healthy comparison subjects matched for age, gender, race, and handedness. Gray matter OFC volumes were measured blind to the diagnoses. As compared to controls, patients had greater volumes in left total OFC (p = 0.048) and left lateral OFC (p = 0.037). Severity of negative symptoms (anhedonia, flattened affect, and alogia) positively correlated with both the left lateral (Spearman's, rho = 0.37, p = 0.019; rho = 0.317, p = 0.041; r = 0.307, p = 0.048, respectively) and the left total OFC (Spearman's, rho = 0.384, p = 0.014; rho = 0.349, p = 0.023; rho = 0.309, p = 0.047, respectively). The present results suggest that first-episode, antipsychotic-naïve schizophrenia subjects exhibit increased OFC volumes that correlate with negative symptoms severity. The OFC, through extensive and complex interconnections with several brain structures with putative role in pathophysiology of schizophrenia including amygdala, hippocampus, thalamus, DLPFC, and superior temporal lobe, may mediate schizophrenia symptoms such as blunting of emotional affect and impaired social functioning. Although the specific neuropathological mechanisms underlying structural abnormalities of the OFC remain unclear, increased OFC volumes might be related to deviations in neuronal migration and/or pruning. Future follow-up studies examining high-risk individuals who subsequently develop schizophrenia at different stages of disease could be especially instructive. © 2007 Elsevier Inc. All rights reserved. Keywords: First-onset schizophrenia; Magnetic resonance imaging (MRI); Neuroimaging; Orbital frontal cortex; Psychosis

1. Introduction Efforts to unravel the precise brain alterations underlying psychiatric disorders in recent years have increasingly employed neuroimaging and neuropathologic techniques. Both neuroimaging and postmortem studies have consistently indicated that schizophrenia is characterized by subtle but significant gray matter abnormalities, particularly affecting frontal and temporal ⁎ Corresponding author. Department of Psychiatry and Behavioral Neurosciences, Wayne State School of Medicine, Detroit, MI, USA. Tel.: +1 313 993 6732; fax: +1 313 577 5900. E-mail address: [email protected] (M.S. Keshavan). 0278-5846/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2006.11.022

lobes (Shenton et al., 2001). A critical role of prefrontal cortex (PFC) in schizophrenia has also been suggested by a number of neuropsychological studies demonstrating deficits in cognitive domains such as executive functions and working memory (for a review see Elvevag and Goldberg, 2000). PFC is, however, a heterogeneous structure both anatomically and functionally, including dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), medial prefrontal cortex, and anterior cingulate. As those subregions appear to be involved in different cognitive processes, it is conceivable to hypothesize that they might be differentially involved in the pathophysiology of schizophrenia. The orbitofrontal cortex, the ventralmost division of PFC, and its reciprocal connections with several brain structures play

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a major role in a wide range of neuropsychological processes, including coding of interoceptive and exteroceptive information, emotional processing and memory, recognition of reinforcing stimuli, stimulus-reward association, reward-guided behavior, mood regulation, impulse control, and control of autonomic and motor effector pathway (Price, 1999; Zald and Kim, 2001). Some of these processes have been reported to be affected in schizophrenia (Bartels and Drake, 1988; Schneider et al., 1995; Stip, 1996). In animals, OFC lesions are associated with aggressive behavior, appetite disturbances, and social withdrawal (Fuster, 1989; Raleigh and Steklis, 1981). In humans, OFC lesions are associated with different emotional disturbances, including apathy, social withdrawal, socially inappropriate behaviors, impairment in the identification of facial and vocal emotional expression, depressed mood, affective instability, and lack of affect (Grafman et al., 1996, 1986; Rolls, 1996). It is interesting to note that most of these symptoms are related to negative symptomatology commonly observed in schizophrenia. Yet, abnormal social behavior is frequently reported as a premorbid feature of the disease, appearing long before its onset (Walker and Lewine, 1990). Despite different lines of evidence supporting a potential role of OFC in the pathophysiology of schizophrenia, only a few neuroimaging studies have examined the anatomical integrity of this structure. They have produced somewhat inconsistent results, with some studies (Chemerinski et al., 2002; Convit et al., 2001; Crespo-Facorro et al., 2000; Goldstein et al., 1999; Gur et al., 2000; Sanfilipo et al., 2000; Szeszko et al., 1999), but not all (Baare et al., 1999; Buchanan et al., 1998; Yamasue et al., 2004), reporting abnormalities in OFC volumes. This apparent discrepancy may be at least partially explained by methodological issues. Firstly, different methods for measuring OFC have been proposed and have reported grossly discrepant values (Lacerda et al., 2003a). Secondly, OFC abnormalities may be specifically related to certain clinical features such as negative symptoms and disturbed social behavior or subgroups of patients (at least one study found volume decrements only in females) (Chemerinski et al., 2002; Crespo-Facorro et al., 2000; Gur et al., 2000). Finally, confounders associated with disease process, drug exposure, and ageing may have hindered significant differences between groups in studies that did not control them. Postmortem neuropathological studies, on the other hand, are faced with additional limitations such as duration of illness prior to death, confounding by concurrent illnesses and perimortem factors (e.g., mode of death, autopsy delay, and tissue processing), diagnosis validity, and availability of enough cases (Harrison, 1999). Since most neuroimaging studies have examined patients with chronic schizophrenia, the question whether OFC abnormalities occur prior to disease onset or are a consequence of disease process and/or treatment is pertinent. Different lines of evidence have supported the neurodevelopmental hypothesis of schizophrenia (Schultz and Andreasen, 1999; Weinberger, 1995). According to this theory, the symptoms of the disorder are a manifestation of either a dysfunctional neural circuitry resulting from early (pre- or perinatal) deviations (Murray and Lewis, 1987; Weinberger, 1987) or disturbed brain maturational

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processes such as pruning in late childhood and adolescence (Keshavan et al., 1994), which are largely not apparent until the onset of symptomatology. In vivo MRI evaluation of firstepisode, drug-naïve subjects propitiates a privileged opportunity to overcome at least part of the methodological problems present in both postmortem studies and MRI studies examining chronic populations described earlier. The present study aimed to investigate anatomical integrity of OFC in first-episode, drug-naïve schizophrenia subjects by using a highly reliable and validated method. We were also particularly interested in identifying possible relationships between OFC volumes and symptom severity. We hypothesized that patients would have smaller OFC as compared to healthy controls and that gray matter volumes inversely correlate with negative symptoms (flattened affect, alogia, anhedonia, and avolition) severity. Correlations between OFC volumes and positive symptoms were not predicted in view of inconsistent data in previous literature (Szeszko et al., 1999; Lacerda et al., 2003a,b). 2. Methods 2.1. Subjects The sample included 43 first-episode, treatment-naïve subjects with DSM-IV diagnosis of schizophrenia (29 males) and 53 healthy controls (34 males). Patients were recruited through the Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center and examined during their first hospitalization, before they were started on antipsychotic drugs. Diagnosis was established using Structured Clinical Interview for DSM-IV — Patient Version (Spitzer et al., 1994). All patients were followed up for at least 6 months to confirm diagnostic stability and obtain additional history. All subjects were given a standard medical examination before the recruitment and provided written informed consent after detailed explanation of the study procedures, which were approved by the University of Pittsburgh School of Medicine Institutional Review Board (IRB). All subjects were physically healthy and did not have a systemic or neurological illness, mental retardation, or head injury. None of the subjects was diagnosed with substance abuse in the previous month or dependence within the previous 6 months. Antipsychotic-naïve status was confirmed based on detailed history taking, collateral information, and diagnostic interviews. 2.2. Clinical ratings Symptom severity was assessed with Brief Psychiatric Rating Scale [BPRS; (Overall and Gorham, 1962)], Scale for the Assessment of Positive Symptoms [SAPS; (Andreasen, 1984)], and Scale for the Assessment of Negative Symptoms [SANS; (Andreasen, 1983)]. 2.3. MRI parameters All scans were acquired at the MRI Center at the University of Pittsburgh Medical Center with a 1.5-T Signa whole body

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scanner (GE Medical Systems, Milwaukee, WI). A sagittal scout series was performed to determine image quality and clarity as well as subject head position. T1-weighted images were acquired by using a three-dimensional spoiled gradient in the steady-state pulse that obtained one-hundred twenty-four 1.5-mm thick contiguous coronal images, with the following image parameters: TR = 25 ms; TE = 5 ms; flip angle = 40°; field of view = 24 cm; matrix size of 256 × 192; NEX = 1. Two-dimensional proton density (PD) and T2-weighted images were acquired using the following parameters: TR = 2500 ms; TE = 17 ms (PD) and 102 ms (T2); field of view = 24 cm; matrix size of 256 × 192; NEX = 1; gap = 0. The MRI data were identified by scan number alone in order to retain blindness and analyzed using BRAINS2 software (Andreasen et al., 1992). Before tracing, scans were spatially realigned, so that the brain anterior–posterior axis was parallel to the intercommissural line, which was horizontal in the sagittal plane, and the interhemispheric fissure vertical in the axial plane. 2.4. Tracing guidelines A detailed description as well as a validation study of the method used to measure OFC is presented elsewhere (Lacerda et al., 2003a). OFC was manually traced in the coronal view. The tip of the genu was identified in the sagittal plane and chosen as the most posterior slice to be traced in the coronal plane. The last slice traced was the most anterior coronal slice where brain tissue could be identified. The superior limit was divided in two parts to reflect the actual anatomical boundary of the OFC. In the subgenual regions, the superior limit was represented by the inferior border of the anterior cingulate corresponding to a midpoint at the interhemispheric fissure five slices (5.08 mm) below the intercommissural line. In the slices ahead of the genu of the corpus callosum, the superior limit was represented by a midpoint placed on the intercommissural line. In all traced slices, horizontal and vertical crosshairs were placed as tangential lines at the inferior and lateral surfaces of the frontal lobes, respectively. Two lateral points were generated by the intersection of these two lines. These lateral points were then connected to the superior limit point in each slice. The lateral borders of tracings were represented by these straight lines connecting lateral points to the superior limit point. The inferior border was traced following the inferior surface of the frontal lobes. The OFC was also subdivided into medial and lateral OFC using the olfactory sulcus as a boundary. This subdivision was not conducted in the most anterior slices, where olfactory sulcus is not present. Therefore, the addition of medial and lateral OFC measures produces smaller values in comparison to total OFC volumes. Total brain volumes (TBVs) were manually traced in coronal slices, including total cerebral gray and white matter. 2.5. Reliability tests OFC and subdivisions were independently traced by two raters (ALTL and OY) in 10 randomly selected scans. Intraclass

correlation coefficients (ICCs) for gray matter OFC measures ranged from 0.976 to 0.997, whereas ICC for TBV measurements was 0.975. 2.6. Validity study As previously reported (Lacerda et al., 2003a), sensitivity of the method for OFC gray matter was 87.7%, while specificity of the method for OFC gray matter was 84.5%. 2.7. Statistical analyses All statistical analyses were conducted using SPSS for Windows software, version 11.5 (SPSS, Chicago, Illinois). Alpha was set at p b 0.05. A two-way ANCOVA was performed with OFC gray matter volumes as dependent measures, diagnosis and gender entered as independent group dimensions, and TBV and age as covariates. Using the same model, we also analyzed male and female subgroups separately. Also, Student's t test was used to compare lateralization indices (patients vs. controls; males vs. females). Categorical measures (e.g., gender, handedness) were compared using Chi-square tests. Spearman correlations were performed to investigate effects of clinical and demographic variables, which were non-normally distributed, such as age, age at onset, duration of prodromal symptoms, and symptom severity as assessed by scales on OFC volumes. In order to protect against multiple comparisons, we restricted correlations to regions showing significant differences between groups. In addition, correlations with positive symptoms, not Table 1 Demographic and clinical characteristics of first-episode schizophrenia patients (N = 43) and healthy controls (N = 53) Variable

Patients

Controls

Statistic

p

Age (years) Gender (M/F) Race Caucasian African American Asian Other Handedness Right Left Mixed TBV Symptom rating scales BPRS Positive symptoms Negative symptoms Total SANS Affective flattening Alogia Avolition-apathy Anhedonia-asociality Attention SAPS Hallucinations Delusions Bizarre behavior

24.52 ± 5.98 29/14

25.29 ± 7.34 34/19

t(94) = 0.55 χ2 = 0.114 χ2 = 4.587

0.58 0.736 0.332

26 12 3 2

40 9 3 0 χ2 = 2.439

0.295

34 4 3 1438 ± 168

43 2 1 1477 ± 131

F1,93 = 2

0.16

15.67 ± 3.82 8 ± 3.36 50.86 ± 9.1 2.8 ± 0.86 2.48 ± 1.02 3.31 ± 0.78 3.4 ± 0.9 2.31 ± 1.05 2.09 ± 1.65 3.21 ± 1.2 1.19 ± 1.38

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Table 2 Uncorrected OFC gray matter volumes in first-episode schizophrenia subjects and healthy controls OFC gray matter volumes (cm3)

Region

Patients (N = 43)

Medial Right Left Lateral Right Left

F1,90

p

Controls (N = 53)

Mean ± SD

Median

Range

Mean ± SD

Median

Range

3.77 ± 0.98 3.3 ± 0.86

3.81 3.41

1.72–6.06 1.64–5.35

3.6 ± 0.88 3.27 ± 0.77

3.48 3.21

1.92–5.69 1.67–5.09

2.946 1.633

0.09 0.205

3.22 ± 0.86 3.53 ± 0.93

3.28 3.45

1.71–5.11 1.92–5.52

3.24 ± 0.76 3.32 ± 0.79

3.26 3.26

1.50–5.14 1.85–5.52

0.311 4.498

0.579 0.037

hypothesized to relate to OFC, were exploratory. Correlations involving negative symptoms, which are hypothesized to relate to OFC functioning, were tested with an alpha level set at p b 0.05. All analyses were two-tailed. 3. Results 3.1. Effect of diagnosis and clinical variables Table 1 shows clinical and demographic characteristics of the sample. There were no significant differences between patients and healthy comparison subjects with regard to age, gender, handedness, or race. The total brain volumes did not differ between the study groups (ANCOVA, with age as a covariate;

patients: 1438 ± 168 mm3, controls: 1477 ± 131 mm3, F1,93 = 2, p = .16). Group comparisons revealed a significant main effect of diagnosis, with first-episode schizophrenia subjects showing increased gray matter volumes in the left lateral OFC (two-way ANCOVA, age and TBV as covariates, F1,90 = 4.498, p = 0.037). Comparisons involving secondary measures (total OFC, patients = 15.54 ± 3.87 vs. controls = 14.97 ± 3.36, F1,90 = 2.723, p = 0.102; right OFC = 7.91 ± 2.04 vs. 7.66 ± 1.76, F1,90 = 1.736, p = 0.191; medial OFC = 7.07 ± 1.69 vs. 6.87 ± 1.61, F1,90 = 2.622, p = 0.109; lateral OFC = 6.75 ± 1.62 vs. 6.56 ± 1.43, F1,90 = 2.282, p = 0.134; ANCOVA, age and TBV as covariates), represented by sums of primary measures, were nonsignificant except for left OFC (7.64 ± 1.96 vs. 7.24 ± 1.81,

Fig. 1. OFC gray matter volumes (corrected for TBV). (A) Left lateral OFC; (B) right lateral OFC; (C) left medial OFC; (D) right medial OFC.

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Table 3 Correlations involving OFC volumes and symptomatology Region Left total rho p Left lateral rho p

Flattened Alogia Anhedonia Hallucination Delusion Bizarre affect behavior 0.317 0.041 ⁎

0.307 0.370 0.048 ⁎ 0.019 ⁎

− 0.041 0.79

0.134 0.39

0.128 0.41

0.349 0.023 ⁎

0.309 0.384 0.047 ⁎ 0.014 ⁎

− 0.070 0.65

0.171 0.26

0.163 0.3

⁎ p b 0.05.

ANCOVA, age and TBV as covariates, F1,90 = 4.021, p = 0.048). OFC gray matter primary measures are summarized in Table 2 and Fig. 1. Comparisons involving lateralization indices (right − left / right + left × 100) were nonsignificant (t test, p N 0.05). Also, there was no gender effect on this measure among patients or controls (t test, p N 0.05). Severity of negative symptoms (anhedonia, flattened affect, and alogia) positively correlated with both the left lateral (Spearman's, rho = 0.37, p = 0.019; rho = 0.317, p = 0.041; r = 0.307, p = 0.048, respectively) and the left total (Spearman's, rho = 0.384, p = 0.014; rho = 0.349, p = 0.023; rho = 0.309, p = 0.047, respectively) OFC volumes. After controlling for handedness, only correlations involving anhedonia and alogia remained significant (left total, rho = 0.37, p = 0.022, rho = 0.35, p = 0.033; left lateral, rho = 0.34, p = 0.035, rho = 0.35, p = 0.031, respectively). Correlations involving positive symptoms severity and left lateral (hallucinations, rho = − 0.041, p = 0.79; delusions, rho = 0.134, p = 0.39; bizarre behavior, rho = 0.128, p = 0.41) and left total volumes (hallucinations, rho = − 0.07, p = 0.65; delusions, rho = 0.175, p = 0.26; bizarre behavior, rho = 0.163, p = 0.3) were nonsignificant. Table 3 summarizes correlations involving symptomatology and OFC volumes. 3.2. Effect of demographic variables Correlations involving age and OFC volumes were nonsignificant (Spearman's, p N 0.05) in analyses involving the entire sample as well as when patients and controls were analyzed separately. Also, no significant effect of gender was found in analyses involving either the entire sample or groups separately (ANCOVA, p N 0.05) No interaction involving diagnosis and gender was observed. 4. Discussion The present results suggest that first-episode, drug-naïve schizophrenia subjects exhibit increased OFC gray matter volumes compared to healthy controls. This difference was significant only in left lateral and left total OFC. Additionally, left lateral as well as left total OFC gray matter volumes correlated positively with severity of negative symptoms. Although we predicted that the OFC volumes would be smaller in schizophrenia patients compared to healthy controls, our findings do not support this hypothesis.

The present findings are conflicting with most previous studies, which have reported either no abnormalities (Baare et al., 1999; Buchanan et al., 1998; Yamasue et al., 2004) or decrease (Chemerinski et al., 2002; Convit et al., 2001; CrespoFacorro et al., 2000; Goldstein et al., 1999; Gur et al., 2000; Sanfilipo et al., 2000) in the OFC volumes. Other studies, however, have also reported increased OFC volumes in schizophrenia (Hege et al., 1997; Szeszko et al., 1999; Woods et al., 1996). Examining a mostly male sample, Woods et al. (1996) found increased OFC volumes in schizophrenia subjects. Similarly, Szeszko et al. (1999) reported increased right OFC in males with first-episode schizophrenia. Moreover, Hege et al. (1997) reported increased right gyrus rectus volumes in males with severe schizophrenia. These discrepancies may be due to different reasons. Firstly, these divergences may be due to methodological differences in defining and measuring the OFC. As mentioned earlier, different methods have been employed for measuring OFC, yielding discrepant values (Lacerda et al., 2003a). In addition, imaging parameters varied considerably among the studies (e.g., spatial resolution varied from 1 mm to 6 mm). Secondly, the differences in patient populations may also be an important factor. Various studies have enrolled only male subjects (Chemerinski et al., 2002; Convit et al., 2001; Crespo-Facorro et al., 2000; Sanfilipo et al., 2000; Wible et al., 2001). Additionally, only two studies (Crespo-Facorro et al., 2000; Szeszko et al., 1999) have examined first-episode subjects, with only one study (Crespo-Facorro et al., 2000) evaluating drugnaïve patients. Treatment with antipsychotic drugs may influence brain volume. In a 1-year follow-up study, examining 34 first-episode patients and 36 healthy controls, Cahn et al. (2002) concluded that there is a progressive loss of gray matter in patients that occurs in the early stages of schizophrenia and is related to both antipsychotic drug use and outcome. More specifically, different studies have suggested that a larger cumulative dosage of antipsychotic drug is associated with progressive decreases in frontal lobe volumes in first-episode schizophrenia subjects (Gur et al., 1998; Madsen et al., 1999). Furthermore, disease process appears to differentially affect brain regions, with sparing of some structures resulting in progressive volume decreases of others (Jacobsen et al., 1998). Specific neuropathologic mechanisms involved in OFC anatomic abnormalities remain unclear. Increased OFC in first-episode, drug-naïve schizophrenia subjects might reflect disordered cellular array due to abnormal cellular migration during brain development (Corfas et al., 2004) or abnormalities in pruning (Keshavan et al., 1994). Studies suggesting abnormal cortical folding in prefrontal regions have supported this hypothesis (Narr et al., 2004; Vogeley et al., 2000). Interestingly, individuals at high risk for developing schizophrenia who subsequently developed schizophrenia showed increased PFC cortical folding as well as disproportionately large PFC volumes as compared to high-risk individuals who remained unaffected (Harris et al., 2004; Vogeley et al., 2001), suggesting both increased PFC folding and volume as risk factors for developing schizophrenia in genetically vulnerable individuals. A recent pilot study (Jou et al., 2005), however, found a decreased PFC

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gyrification index in high-risk individuals, although the predictive value of this finding for subsequent development of schizophrenia was not examined. Deviations in normal maturational processes have also been proposed as potentially relevant in the pathophysiology of schizophrenia. These processes mainly involve exaggerated synaptic production during early childhood and disturbed synaptic elimination in brain regions involved in cognitive processes (Keshavan et al., 1994). A defective pruning might, thus, contribute to increased OFC volumes. Considering the present findings suggesting increased OFC volumes in first-episode, drug-naïve subjects and previous studies reporting decreased OFC in chronic schizophrenics, one might speculate that initially increased OFC volumes would be associated to neurodevelopmental deficits (aberrant cellular migration and/or defective pruning), whereas decreased OFC would be related to disease (neurodegenerative) process and drug exposure. Correlational analyses involving OFC volumes and both demographic and clinical variables showed associations only with negative symptoms (flattened affect, alogia, and anhedonia). Although in an opposite direction (inverse correlations), different studies have also reported significant correlations between OFC volumes and negative symptoms (Baare et al., 1999; Gur et al., 2004; Sanfilipo et al., 2000) or social functioning (Chemerinski et al., 2002). The OFC, through extensive and complex interconnections with several brain structures with putative role in pathophysiology of schizophrenia including amygdala, hippocampus, thalamus, DLPFC, and superior temporal lobe, may mediate schizophrenia symptoms such as blunting of emotional affect and impaired social functioning (Zald and Kim, 2001). In fact, OFC lesions in humans have been associated with disrupted social and emotional behavior. Deficits commonly observed in schizophrenia such as lack of affect, social inappropriateness, and deficits in reasoning and judgment are among the most common sequelae of OFC damage in humans (Hornak et al., 2003; Rolls, 1996). The present findings should be interpreted with caution in view of some limitations. First, the olfactory sulcus represented the boundary between medial and lateral OFC. Although there is no widely accepted anatomic landmark for subdividing the OFC, using the olfactory sulcus as a reference proved to be highly reliable but may not reflect the actual border of these subdivisions (Lacerda et al., 2003a). Additionally, this subdivision was not conducted in the most anterior slices, where the olfactory sulcus is not present. Second, as the lateral boundaries of tracings were represented by straight lines, the most lateral parts of OFC were more likely to be excluded from measurements. Finally, to our knowledge, this is the first study to separately examine both medial and lateral OFC in schizophrenia, reporting an increased left lateral OFC. Independent replication of the present findings is needed. In summary, first-episode, drug-naïve schizophrenics had volume increases in left total and left lateral OFC gray matter in comparison with healthy controls. In addition, there were positive correlations between volumes of those regions and negative, but not positive, symptoms. The OFC, through extensive interconnections with several brain structures with

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putative role in pathophysiology of schizophrenia, may mediate negative symptoms such as flattened affect and anhedonia, which are commonly described as sequelae of OFC damage. Although specific neuropathologic mechanisms involved in OFC anatomic abnormalities remain unclear, increased OFC volumes might be related to deviations in neuronal migration and/or pruning. Future follow-up studies examining high-risk individuals who subsequently develop schizophrenia at different stages of disease could be especially instructive. Acknowledgments This publication was supported by funds received from MH 45156 and the NIH/NCRR/GCRC grant #M01 RR00056. We thank Drs. Cameron S. Carter MD, Gretchen Haas PhD, Nina R. Schooler PhD, and the clinical core staff of the Center for the Neuroscience of Mental Disorders (MH 45156) for their assistance in diagnostic and psychopathological assessments. References Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS). Iowa City, IA: University of Iowa; 1983. Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS). Iowa City, IA: University of Iowa; 1984. Andreasen NC, Cohen G, Harris G, Cizadlo T, Parkkinen J, Rezai K, et al. Image processing for the study of brain structure and function: problems and programs. J Neuropsychiatry Clin Neurosci 1992;4:125–33. Baare WF, Hulshoff Pol HE, Hijman R, Mali WP, Viergever MA, Kahn RS. Volumetric analysis of frontal lobe regions in schizophrenia: relation to cognitive function and symptomatology. Biol Psychiatry 1999;45:1597–605. Bartels SJ, Drake RE. Depressive symptoms in schizophrenia: comprehensive differential diagnosis. Compr Psychiatry 1988;29:467–83. Buchanan RW, Vladar K, Barta PE, Pearlson GD. Structural evaluation of the prefrontal cortex in schizophrenia. Am J Psychiatry 1998;155:1049–55. Cahn W, Pol HE, Lems EB, van Haren NE, Schnack HG, van der Linden JA, et al. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry 2002;59:1002–10. Chemerinski E, Nopoulos PC, Crespo-Facorro B, Andreasen NC, Magnotta V. Morphology of the ventral frontal cortex in schizophrenia: relationship with social dysfunction. Biol Psychiatry 2002;52:1–8. Convit A, Wolf OT, de Leon MJ, Patalinjug M, Kandil E, Caraos C, et al. Volumetric analysis of the pre-frontal regions: findings in aging and schizophrenia. Psychiatry Res 2001;107:61–73. Corfas G, Roy K, Buxbaum JD. Neuregulin 1-erbB signaling and the molecular/ cellular basis of schizophrenia. Nat Neurosci 2004;7:575–80. Crespo-Facorro B, Kim J, Andreasen NC, O'Leary DS, Magnotta V. Regional frontal abnormalities in schizophrenia: a quantitative gray matter volume and cortical surface size study. Biol Psychiatry 2000;48:110–9. Elvevag B, Goldberg TE. Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol 2000;14:1–21. Fuster JM. The prefrontal cortex. New York: Raven Press; 1989. Goldstein JM, Goodman JM, Seidman LJ, Kennedy DN, Makris N, Lee H, et al. Cortical abnormalities in schizophrenia identified by structural magnetic resonance imaging. Arch Gen Psychiatry 1999;56:537–47. Grafman J, Vance SC, Weingartner H, Salazar AM, Amin D. The effects of lateralized frontal lesions on mood regulation. Brain 1986;109:1127–48. Grafman J, Schwab K, Warden D, Pridgen A, Brown HR, Salazar AM. Frontal lobe injuries, violence, and aggression: a report of the Vietnam head injury study. Neurology 1996;46:1231–8. Gur RE, Cowell P, Turetsky BI, Gallacher F, Cannon T, Bilker W, et al. A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 1998;55:145–52.

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