FORNIX IN FIRST EPISODE SCHIZOPHRENIA: A DIFFUSION TRACTOGRAPHY STUDY Background: Fornix, the most prominent white matter output from the hippocampus have been investigated in schizophrenia, and results suggest bilateral disruption of fornix integrity in chronic patients. Since some studies suggest disease related progressive white matter changes, the purpose of this study was to investigate fornix integrity in first episode patients with schizophrenia and first episode of bipolar disorder (manic with psychotic features). Methods: DTI-MRI and fiber tractography were used to evaluate the fornix in 15 schizophrenic patients, 15 bipolar patients, and 18 healthy controls, matched on age, parental socioeconomic status, education and handedness. Mean Fractional Anisotropy for the left and the right fornix were extracted, and compared between groups. Results: Unlike in our previous study of chronic schizophrenia, repeated ANOVA analysis demonstrated no group (P=0.91), or group by side (P=0.66) differences. Conclusions: Diffusion tensor imaging and tractography are valuable tools for studying white matter structures in schizophrenia. Our results suggest a lack of fornix abnormalities at the onset of schizophrenia, indicating that white matter changes in this structure appear later, during the course of the disease. White matter fiber tracts, especially those interconnecting the frontal and temporal lobes, are likely implicated in schizophrenia. Very few studies, however, have focused on the fornix, a compact bundle of white matter fibers, projecting from the hippocampus to the septum, anterior nucleus of the thalamus and the mamillary bodies (Figure 1). Diffusion Tensor Imaging (DTI) (Figure 2), and a new post- processing method, fiber tractography, provide a unique opportunity to visualize and to quantify entire trajectories of fiber bundles, such as the fornix, in vivo. We applied these techniques to quantify fornix anisotropy in schizophrenia. ABSTRACT BACKGROUND METHODS RESULTS REFERENCES CONCLUSIONS 22 Fitzsimmons J 1, Smith K 1, Kubicki M 1,2, San Jose R 3, Westin C-F 3, Salisbury D 4, Kikinis R 3, McCarley RW 2, Shenton ME 1,2,3 Figure 1. The fibers begin in the hippocampus on each side of the brain, the separate left and right side are each called the crux of the fornix. The bundles of fibers come together in the midline of the brain, forming the body of the fornix. 1.Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. 2.Department of Psychiatry, VA Boston healthcare System, Harvard Medical School, Boston, MA. 3.Surgical Planning Laboratory, MRI Division, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. 4.Cognitive Neuroscience Laboratory, Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA. ANOVA FA Calabrese P, Markowitsch HJ, Harders AG, Scholz M, Gehlen W (1995): Fornix damage and memory: A case report. Cortex 31: Chance SA, Highley JR, Esiri MM, Crow TJ (1999): Fiber content of the fornix in schizophrenia: lack of evidence for a primary limbic encephalopathy. Am J Psychiatry 156: Dusek JA, Eichenbaum H (1997): The hippocampus and memory for orderly stimulus relations. Proc Natl Acad Sci U S A 94: Egan MF, Duncan CC, Suddath RL, Kirch DG, Mirsky AF, Wyatt RJ (1994): Event-related potential abnormalities correlate with structural brain alterations and clinical features in patients with chronic schizophrenia. Schizophr Res 11: Gaffan D (1994): Dissociated effects of perirhinal cortex ablation, fornix transection and amygdalectomy: evidence for multiple memory systems in the primate temporal lobe. Exp Brain Res 99: Gaffan D, Harrison S (1989): Place memory and scene memory: effects of fornix transection in the monkey. Exp Brain Res 74: Kuroki N, Kubicki M, Nestor PG, et al (2006): Fornix integrity and hippocampal volume in male schizophrenic patients. Biol Psychiatry 60: Zahajszky J, Dickey CC, McCarley RW, et al (2001): A quantitative MR measure of the fornix in schizophrenia. Schizophr Res 47: Mean (standard deviation)‏ Schizophren ics n = 15 Bipolar n = 15 Controls n = 18 P Value Sex(% Male)‏ 60%61.10%60%- Age25.6(7.26)‏24.22(3.86)‏23.4(5.68)‏0.564 PSES1.27(.59)‏1.56(.86)‏1.47(.64)‏0.51 Handedness (% Right)‏ 100% - Education13.53(2.03)‏14.83(1.5)‏14.2(1.57)‏0.104 Kleenex Newspaper Figure 3. When water molecules aren’t restricted in a specific direction like in the Kleenex or in gray matter the diffusivity is isotropic. When there is restriction in water molecules, as in the newspaper fibers or in myelinated sheathed fiber tracts, the diffusion is anisotropic. Figure 2. DTI offers a way to examine the water diffusion inside the brain. Subjects: DTI and fiber tractography were used to evaluate fornix in 15 schizophrenic patients, 15 affective psychosis patients, and 18 healthy controls, group matched on age, parental socioeconomic status and handedness. (See Table 1)‏ ROI placement: Regions of interest were drawn manually, blind to diagnosis, in order to guide tractography for tracking the fornix bilaterally from the crux through its posterior aspects. Through these regions of interests, Fractional Anisotropy (FA) (Figure 3), a measure of fiber integrity, was then calculated and averaged over the entire tract for each subject.(Figure 4)‏ DTI acquisition: MR scans were conducted using a quadrature head coil on a 1.5- Telsa GE (Echo speed system). The following scan parameters were used: field of view 220x165mm; 128x96 scan matrix (256x192 image matrix), slice thickness=4mm, interslice distance=1mm; receiver band width +/- 4kHz, echo time=64msec, repetition time=2592msec; scan time=60sec per slice section. We acquired coronal slices covering the entire brain. Sensitivity tool: The goal of using this tool is to eliminate fibers with a low degree of inclusion on the selected ROI. The negative findings of this study suggest that in early stages of schizophrenia there is no disruption to the integrity of the fornix, further suggesting that these abnormalities appear later, with progression of the illness. EffectP Value Side X group Group0.910 Figure 4. Region of interest used to extract the fornix, along with the tracts. Table1. Demographics Table 2. FA for First Episode Schizophrenics vs. Healthy Controls Table 3. FA for Chronic Schizophrenics vs. Healthy Controls Table 4. ANOVA Isotropic DiffusionAnisotropic Diffusion