1. Orbitofrontal Cortex Abnormalities in Bipolar Disorder Adolescents. Pablo Najt Department of Psychiatry, University of Texas, Health Science Center at San Antonio.

2. Role of OFC Neuropsychologic functioning: exteroreceptive and interoreceptive information coding reward-guided behavior impulse control mood regulation

3. Anatomical Studies of OFC in Mood Disorders Rajkoswska et al 1999: significant decrease in the thickness of OFC in MDD patients compared with healthy controls (post mortem study). Lai et al 2000 and Bremner et al 2002: bilateral reductions of OFC volumes in MDD patients compared with controls. Lacerda et al 2004: smaller gray matter volumes in right medial and left lateral OFC in MDD patients. And males, but not females patients exhibited smaller left and right medial OFC volumes compared with healthy controls. No studies in BP patients, we expect to find OFC reductions in this condition as well. Bremner (2002): Reduced volume of orbitofrontal cortex in major depression. Biol Psychiatry 51:273-79 Lacerda et al (2004): Anatomical evaluation of the orbitofrontal cortex in major depressive disorder. Biol Psychiatry 55: 353-58

4. 14 children and adolescents with bipolar disorder (mean age ± S.D. = 15.5 ± 3.2 years) 20 healthy controls (mean age ± S.D. = 16.9 ± 3.8 years). Structured Clinical Interview for DSM IV (SCID) for patients aged 18-21 Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime Version (K-SADS-PL) interview for patients younger than 18. Subjects

5. Demographics in Bipolar Patients (BP) and Healthy Controls (HC) VariableBP (n=14)HC (n=20) Age, mean (S.D.) years 15 (3)17 (4) Sex, N (%) female8 (54) 9 (45) Race, N (%) White14 (93)17 (85)

6. Clinical characteristics of patients Age at onsetAgeDxMood st.No. episodes 11921BD ID? 21719BD IE2 31410BD IE3 41215BD IE? 51521BD IE4 61014BD IE6 7818BD IE7 81014BD IE3 9417BD IE5 101213BD IE3/9 111418BD IE4 121114BD IIE9 13 10BD IIE6 14717BD NOSD3

7. 7 Treatment parameters NMinimumMaximumStd. Dev. Lithium dos (mg/day) 96751350248.8 Weeks on Lithium9820871.3 Dose Valproate85001109540.5 VPA blood level (Microgram/ml) 4498632 Weeks on VPA71015051.8

8. 8 MRI Procedures A 1.5 T GE Signa Imaging System running version Signa 5.4.3 software was used to acquire the MRI scans. TR = 25ms, TE = 5ms, nutation angle = 40°, FOV = 24cm, slice thickness = 1.5mm, NEX = 1, matrix size=256x192 Trained raters, who achieved ICC > 0.95, did all anatomical measurements, blindly, with the BRAINS2 software, developed at the University of Iowa Hospitals and Clinics (Andreasen et al 1992). We measured the volumes of OFC (total and gray matter) and its subdivisions.

9. Delimitation of the Orbitofrontal Cortex Starting point Last slice

10. Superior boundary

11. Results-1 Bipolar patients and healthy controls only were compared on demographics (age and race). For clinical variables (diagnosis, family psychiatric history, treatment) male and female patients were compared. No significant differences regarding demographic or clinical variables.

12. Results-2 Analysis of the the young subjects (age<19) only showed the same two effects when analysing the entire sample. No significant differences when combining males and females into one group.

13. (ANCOVA, ICV and age as covariates) Table1. Orbitofrontal Cortex (OFC), Gray Matter Volumes in Female Patients with Bipolar Disorder and Healthy Subjects. Gray matter Volumes(cm³) (Mean + SD) Patients Controls Region(n = 8)(n = 9)p Total OFC18.35 + 3.3614.18 + 4.330.110 Right9.70 + 2.01 7.75 + 2.660.300 Left 8.82 + 1.47 6.54 + 1.810.034 Medial OFC7.73 + 1.55 6.13 + 1.560.135 Right4.18 + 0.8113.32 + 0.900.179 Left3.56 + 0.78 2.82 + 0.720.127 Lateral OFC 6.3 + 1.38 4.33 + 1.240.012 Right3.16 + 0.69 2.4 + 0.750.072 Left3.13 + 0.79 1.92 + 0.530.007

14. Table2. Orbitofrontal Cortex (OFC), Gray Matter Volumes in Male Patients with Bipolar Disorder and Healthy Subjects. Gray matter Volumes( cm³ ) with in (Mean + SD) Patients Controls Region(n= 7) (n= 11)p Total OFC17.49 + 4.3619.76 + 3.140.105 Right9.05 + 2.6510.46 + 1.820.069 Left8.54 + 1.919.44 + 1.730.228 Medial OFC5.88 + 2.697.97 + 0.780.010 Right3.03 + 1.494.17 + 0.470.009 Left3.25 + 1.43.89 + 0.420.133 Lateral OFC5.18 + 0.786.46 + 1.520.047 Right2.7 + 0.553.42 + 0.540.014 Left2.47 + 0.543.04 + 1.050.193 (ANCOVA, ICV and age as covariates)

15. Conclusions Our findings have similarities with previous studies, reporting reductions in medial and lateral OFC gray matter in male patients comparing with controls. While MDD studies observed no differences within the female subgroup between patients and controls, we found larger OFC volumes in female bipolar patients. Further investigation of the OFC in bipolar disorder, confirming these findings is warranted.