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Original Article |

Thalamocortical Disconnection in the Orbitofrontal Region Associated With Cortical Thinning in Schizophrenia

Manabu Kubota, MD; Jun Miyata, MD, PhD; Akihiko Sasamoto, MD; Genichi Sugihara, MD, PhD; Hidefumi Yoshida, MD; Ryosaku Kawada, MD; Shinsuke Fujimoto, MD; Yusuke Tanaka, MD; Nobukatsu Sawamoto, MD, PhD; Hidenao Fukuyama, MD, PhD; Hidehiko Takahashi, MD, PhD; Toshiya Murai, MD, PhD
JAMA Psychiatry. 2013;70(1):12-21. doi:10.1001/archgenpsychiatry.2012.1023.
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Context  Dysfunction of the thalamocortical pathway has been proposed as a putative underlying pathology of schizophrenia. Although the mechanisms involved remain unclear, postmortem studies suggest the involvement of altered neural projections from the thalamus to layers within the prefrontal cortex.

Objectives  To investigate thalamocortical connectivity in schizophrenia and to examine its possible association with cortical thinning in vivo.

Design  Case-control cross-sectional study.

Setting  Department of Psychiatry at Kyoto University Hospital, Japan.

Patients and Other Participants  A total of 37 patients with schizophrenia and 36 age-, sex-, and education-matched healthy controls recruited from the local community underwent diffusion-weighted imaging and T1-weighted 3-dimensional magnetic resonance imaging.

Main Outcome Measures  Probabilistic tractography was performed to investigate thalamocortical pathways. Group differences in mean fractional anisotropy (FA) values were examined in the entire thalamocortical pathway, the thalamolateral prefrontal pathway, the thalamomedial prefrontal pathway, and the thalamo-orbitofrontal pathway. Surface-based analysis was performed to investigate cortical thickness, and the correlation between FA values and cortical thickness was examined.

Results  The patient group exhibited reduced FA values within the right thalamo-orbitofrontal pathway (P < .05 for the 8 group comparisons of FA, Bonferroni correction). In the patient group only, the mean FA value for this pathway was positively correlated with thickness of the right frontal polar and lateral orbitofrontal cortices (P < .05, clusterwise correction).

Conclusions  These results suggest that, in schizophrenia, regional thalamocortical white matter pathology is specifically associated with cortical pathology in regions where fibers connect.

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Figures

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Figure 1. Examples of fiber-tracking results. The entire left thalamocortical pathway (A), the right thalamolateral prefrontal pathway (B), the left thalamomedial prefrontal pathway (C), and the right thalamo-orbitofrontal pathway (D) are shown in green, light blue, brown, and dark blue, respectively. The thalami are shown in red.

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Grahic Jump Location

Figure 2. A, Statistical maps showing reduced cortical thickness in patients with schizophrenia relative to controls. The maps are shown for the right and left hemispheres in the lateral and medial views, respectively. Significant regions are shown in red-yellow (P < .05, clusterwise correction). B, Regions of significant reduction in fractional anisotropy (FA) in patients. To aid visualization, the results were thickened using the tbss_fill script implemented in FMRIB Software Library version 4.1.6 (red-yellow) and are shown overlaid on the mean FA maps and FA skeleton (green) (P < .05, corrected by means of threshold-free cluster enhancement37).

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Grahic Jump Location

Figure 3. Results of correlational analyses. A, Statistical maps showing the regions of cortical thickness positively correlated with fractional anisotropy (FA) for the right thalamo-orbitofrontal pathway in the patient group. Significant regions (the right frontal polar and lateral orbitofrontal cortices) are shown in red (P < .05, clusterwise correction). B, A group-based thalamocortical map for the right thalamo-orbitofrontal pathway in patients. The pathway is shown in 3-dimensional and horizontal images (dark blue), together with the right thalamus (red) and the right frontal polar (light blue) and lateral orbitofrontal (green) cortices. C, Scatterplots and regression slopes of cortical thickness with FA for the right thalamo-orbitofrontal pathway. The patient group exhibited significant FA-thickness correlations in the right frontal polar and lateral orbitofrontal cortices. However, no such correlations were found for the controls.

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