Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup

Huggins, A. A.; Baird, C. L.; Briggs, M.; Laskowitz, S.; Fouda, S.; Haswell, C. C.; Sun, D.; Salminen, L. E.; Jahanshad, N.; Thomopoulos, S. I.; Veltman, D. J.; Frijling, J. L.; Olff, M.; van Zuiden, M.; Koch, S. B. J.; Nawijn, L.; Wang, L.; Zhu, Y.; Li, G.; Stein, D. J.; Ipser, J.; Seedat, S.; du Plessis, S.; van den Heuvel, L. L.; Suarez-Jimenez, B.; Zhu, X.; Kim, Y.; He, X.; Zilcha-Mano, S.; Lazarov, A.; Neria, Y.; Stevens, J. S.; Ressler, K. J.; Jovanovic, T.; van Rooij, S. J. H.; Fani, N.; Hudson, A. R.; Mueller, S. C.; Sierk, A.; Manthey, A.; Walter, H.; Daniels, J. K.; Schmahl, C.; Herz

doi:10.1101/2022.10.13.512111

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bioRxiv · 10.1101/2022.10.13.512111

Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup

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Abstract

BackgroundThe cerebellum critically contributes to higher-order cognitive and emotional functions such fear learning and memory. Prior research on cerebellar volume in PTSD is scant and has neglected neuroanatomical subdivisions of the cerebellum that differentially map on to motor, cognitive, and affective functions. MethodsWe quantified cerebellar lobule volumes using structural magnetic resonance imaging in 4,215 adults (PTSD n= 1640; Control n=2575) across 40 sites from the from the ENIGMA-PGC PTSD working group. Using a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation, we obtained volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum total and subregional volume in PTSD compared to healthy controls. The Benjamini-Hochberg procedure was used to control the false discovery rate (p-FDR < .05). ResultsPTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume. In addition, people with PTSD showed reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), but also the vermis (VI, VIII), flocculonodular lobe (lobule X), and cerebellar white matter (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. ConclusionsThese findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in high-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

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Huggins, A. A., Baird, C. L., Briggs, M., Laskowitz, S., Fouda, S., Haswell, C. C., Sun, D., Salminen, L. E., Jahanshad, N., Thomopoulos, S. I., Veltman, D. J., Frijling, J. L., Olff, M., van Zuiden, M., Koch, S. B. J., Nawijn, L., Wang, L., Zhu, Y., Li, G., Stein, D. J., Ipser, J., Seedat, S., du Plessis, S., van den Heuvel, L. L., Suarez-Jimenez, B., Zhu, X., Kim, Y., He, X., Zilcha-Mano, S., Lazarov, A., Neria, Y., Stevens, J. S., Ressler, K. J., Jovanovic, T., van Rooij, S. J. H., Fani, N., Hudson, A. R., Mueller, S. C., Sierk, A., Manthey, A., Walter, H., Daniels, J. K., Schmahl, C., Herz. 2022-10-17. Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup. https://doi.org/10.1101/2022.10.13.512111

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