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

Huggins, Ashley A.; Baird, C. Lexi; Briggs, Melvin; Laskowitz, Sarah; Fouda, Samar; Haswell, Courtney C.; Sun, Delin; Salminen, Lauren E.; Jahanshad, Neda; Thomopoulos, Sophia I; Veltman, Dick J.; Frijling, Jessie L.; Olff, Miranda; Zuiden, Mirjam van; Koch, Saskia B.J.; Nawijn, Laura; Wang, Li; Zhu, Ye; Li, Gen; Stein, Dan J.; Ipser, Jonathan; Seedat, Soraya; Plessis, Stéfan du; Heuvel, Leigh van den; Suarez‐Jimenez, Benjamin; Zhu, Xi; Kim, Yoojean; He, Xiaofu; Zilcha‐Mano, Sigal; Lazarov, Amit; Neria, Yuval; Stevens, Jennifer S.; Ressler, Kerry J.; Jovanović, Tanja; Rooij, Sanne J.H. van; Fani, Negar; Hudson, Anna R.; Mueller, Sven C.; Sierk, Anika; Manthey, Antje; Walter, Henrik; Daniels, Judith K.; Schmahl, Christian; Herzog, Julia; Říha, Pavel; Rektor, Ivan; Lebois, Lauren A. M.; Kaufman, Milissa L.; Olson, Elizabeth A.; Baker, Justin T.; Rosso, Isabelle M.; King, Anthony P.; Liberzon, Isreal; Angstadt, Mike; Davenport, Nicholas D.; Sponheim, Scott R.; Disner, Seth G.; Straube, Thomas; Hofmann, David; Qi, Rongfeng; Lu, Guang Ming; Baugh, Lee A.; Forster, Gina L.; Simons, Raluca M.; Simons, Jeffrey S.; Magnotta, Vincent A.; Fercho, Kelene A.; Maron‐Katz, Adi; Etkin, Amit; Cotton, Andrew S.; O'Leary, Erin N.; Xie, Hong; Wang, Xin; Quidé, Yann; El‐Hage, Wissam; Lissek, Shmuel; Berg, Hannah; Bruce, Steven E.; Cisler, Josh M.; Ross, M. A.; Herringa, Ryan J.; Grupe, Daniel W.; Nitschke, Jack B.; Davidson, Richard J.; Larson, Christine L.; deRoon‐Cassini, Terri; Tomas, Carissa W.; Fitzgerald, Jacklynn M.; Blackford, Jennifer Urbano; Olatunji, Bunmi O.; Kremen, William S.; Lyons, Michael J.; Franz, Carol E.; Gordon, Evan M.; May, Geoffrey; Nelson, Steven M.; Abdallah, Chadi G.; Levy, Ifat; Harpaz‐Rotem, Ilan; Krystal, John H.; Dennis, Emily L.; Tate, David F.; Cifu, David X.; Walker, William C.; Wilde, Elisabeth A.; Harding, Ian H.; Kerestes, Rebecca; Thompson, Paul M.; Morey, Rajendra A.

doi:10.1101/2022.10.13.512111

Cited by 2 publications

(2 citation statements)

References 111 publications

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“…[44][45][46] Two recent examinations in ENIGMA working groups have shown deficits related to PTSD and epilepsy, primarily in the posterior lobe. 36,47 In contrast to these previous investigations involving adult clinical populations, our results offer novel findings from a relatively large, pediatric brain injury population. Further analyses with expanded age ranges and multi-modal MRI data may be able to disentangle these potential sources of susceptibility.…”

Section: Cerebellum Developmentmentioning

confidence: 58%

Multimodal Analysis of Secondary Cerebellar Alterations after Pediatric Traumatic Brain Injury

Keleher

Lindsey

Kerestes

et al. 2022

Preprint

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While traditionally ignored as a region purely responsible for motor function, the cerebellum is increasingly being appreciated for its contributions to higher-order functions through cerebro-cerebellar networks. Traumatic brain injury (TBI) research generally focuses on the cerebrum, in part because of the frequency of acute pathology. Acute pathology is an important predictor of outcome, but neural disruption evolves over time in ways that influence daily-life functioning. We examine these changes in a multi-modal, multi-cohort study. Combining 12 datasets from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Pediatric msTBI (moderate-severe TBI) working group, we measured volume of the total cerebellum and 17 subregions using a state-of-the-art, deep learning-based approach for automated parcellation in 598 children and adolescents with or without TBI (msTBI; n = 314 | non-TBI; n = 284; age M = 14.0 +/- 3.1 years). Further, we investigated brain-behavior relations between cerebellar volumes and a measure of executive functioning (Behavioral Rating Inventory of Executive Function). In a subsample with longitudinal data (n = 80), we assessed associations between late changes in cerebellar volume and early white matter (WM) microstructure using diffusion tensor imaging (DTI). Significantly smaller total cerebellar volume was observed in the msTBI group (Cohens d = -0.37). In addition, smaller volume was found in posterior lobe regions including crus II, lobule VIIB and VIIIB, and vermis VII and IX (Cohens d range = -0.22 to -0.43). These alterations were primarily driven by participants in the chronic phase of injury (> 6 months). Smaller cerebellum volumes were associated with more parent-reported executive function problems. In a subset of participants with longitudinal data, we found evidence of altered growth in total cerebellum volume, with younger msTBI participants showing secondary degeneration (volume reductions), and older participants showing disrupted development (slower growth rates). Changes in total cerebellum volume over time were also associated with WM microstructure in the first months post-injury, such that poorer WM organization in the first months post-injury was associated with decreases in volume longitudinally. Pediatric msTBI was characterized by smaller cerebellar volumes, primarily in the posterior lobe and vermis. The course of these alterations, along with group differences in longitudinal volume changes and injury-specific associations between DTI measures and volume changes, suggests secondary cerebellar atrophy, possibly related to supratentorial lesions, and/or disruption in cerebellar structural and functional circuits. Moreover, evidence for brain-behavior relationships underscore the potential cognitive and behavioral consequences of cerebellar disruption during a critical period of brain development.

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Section: Cerebellum Developmentmentioning

confidence: 58%

Multimodal Analysis of Secondary Cerebellar Alterations after Pediatric Traumatic Brain Injury

Keleher

Lindsey

Kerestes

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…However, the posterior cerebellum may simply be particularly susceptible to disruption, perhaps due to connectivity with the prefrontal cortex . Two recent examinations in ENIGMA working groups have shown volume deficits among adults with posttraumatic stress disorder and epilepsy, primarily in the posterior lobe . Future analyses with expanded age ranges and multimodal MRI data may further disentangle potential sources of susceptibility.…”

Section: Discussionmentioning

confidence: 98%

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury

Keleher,

Lindsey,

Kerestes

et al. 2023

JAMA Netw Open

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ImportanceTraumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning.ObjectiveTo investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function.Design, Setting, and ParticipantsThis retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022.ExposureAccidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury.Main Outcomes and MeasuresVolume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning.ResultsA total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = −0.37; 95% CI, −0.52 to −0.22; P &lt; .001) and subregional cerebellum volumes (eg, corpus medullare; d = −0.43; 95% CI, −0.58 to −0.28; P &lt; .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, &gt;6 months postinjury) of injury (total cerebellar volume, d = −0.55; 95% CI, −0.75 to −0.35; P &lt; .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (β = −208.9 mm3; 95% CI, −319.0 to −98.0 mm3; P = .008) and Metacognition Index score (β = −202.5 mm3; 95% CI, −319.0 to −85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (β = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (β=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005).Conclusions and RelevanceIn this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

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

Cited by 2 publications

References 111 publications

Multimodal Analysis of Secondary Cerebellar Alterations after Pediatric Traumatic Brain Injury

Multimodal Analysis of Secondary Cerebellar Alterations after Pediatric Traumatic Brain Injury

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury

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