Abstract
Disrupted topological organization of brain functional networks has been widely reported in bipolar disorder. However, the potential clinical implications of structural connectome abnormalities have not been systematically investigated. The present study included 109 unmedicated subjects with acute mania who were assigned to 8 weeks of treatment with quetiapine or lithium and 60 healthy controls. High resolution 3D-T1 weighted magnetic resonance images (MRI) were collected from both groups at baseline, week 1 and week 8. Brain networks were constructed based on the similarity of morphological features across brain regions and analyzed using graph theory approaches. At baseline, individuals with bipolar disorder illness showed significantly lower clustering coefficient (Cp) (p = 0.012) and normalized characteristic path length (λ) (p = 0.004) compared to healthy individuals, as well as differences in nodal centralities across multiple brain regions. No baseline or post-treatment differences were identified between drug treatment conditions, so change after treatment were considered in the combined treatment groups. Relative to healthy individuals, differences in Cp, λ and cingulate gyrus nodal centrality were significantly reduced with treatment; changes in these parameters correlated with changes in Young Mania Rating Scale scores. Baseline structural connectome matrices significantly differentiated responder and non-responder groups at 8 weeks with 74% accuracy. Global and nodal network alterations evident at baseline were normalized with treatment and these changes associated with symptomatic improvement. Further, baseline structural connectome matrices predicted treatment response. These findings suggest that structural connectome abnormalities are clinically significant and may be useful for predicting clinical outcome of treatment and tracking drug effects on brain anatomy in bipolar disorder.
Clinical Trials Registration: Name: Functional and Neurochemical Brain Changes in First-episode Bipolar Mania Following Successful Treatment with Lithium or Quetiapine. URL: https://clinicaltrials.gov/. Registration number: NCT00609193. Name: Neurofunctional and Neurochemical Markers of Treatment Response in Bipolar Disorder. URL: https://clinicaltrials.gov/. Registration number: NCT00608075.
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Funding
This research was supported by NIMH grants P50MH077138, R01MH080973, and R01MH078043; and a grant from AstraZeneca Pharmaceuticals. Funding sources had no role in the design and conduct of this study; collection, management, analysis, and interpretation of the data; preparation, review, approval of the manuscript; or decision to submit the manuscript for publication.
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DL and WBL analyzed the image data and drafted the manuscript. MJT, LRP, JAW, JRS, ER, FGN, DEF, SMS, MPD, and CMA designed the study and collected clinical and image data. SL, QYG, and JAS contributed to data analysis and manuscript writing. All authors reviewed and approved the manuscript for submission.
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FGN spouse is an employee at Eli Lilly and Co. FGN himself reported no conflicts of interests. JRS has received research support from the National Institutes of Health (NIMH/NIEHS/NICHD) as well as AbbVie, Neuronetics, and Otsuka. He has received material support from and provided consultation to Myriad Genetics and receives royalties from the publication of two texts (Springer) and serves as an author for UpToDate and an Associate Editor for Current Psychiatry. He has spoken in CME presentations for Neuroscience Education Institute, MedScape, American Academy of Child & Adolescent Psychiatry, American Academy of Pediatrics, and CMEology. Finally, JRS also has provided consultation to the FDA and Intracellular Therapeutics. JAS consults to VeriSci. LRP has received research support from Acadia, Allergan, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sunovion and Supernus. MPD is on the lecture bureau for Sunovion; has received research support from Alkermes, Acadia, Allergan, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sunovion and Supernus; and has provided consultation or advisory board services for Alkermes, Allergan, Assurex, CMEology, Janssen, Johnson and Johnson, Lundbeck, Myriad, Neuronetics, Otsuka, Pfizer, Sunovion and Supernus. CMA has spoken for Otsuka and Janssen. He has received research support from Merck, Forest, and Alkermes, and provided consultation for Janssen. SMS chairs Data Safety and Monitoring Boards for Sunovion and has grant funding (through the University of Texas) from Janssen. All other authors declare that they have no potential conflicts of interest.
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Lei, D., Li, W., Tallman, M.J. et al. Changes in the structural brain connectome over the course of a nonrandomized clinical trial for acute mania. Neuropsychopharmacol. 47, 1961–1968 (2022). https://doi.org/10.1038/s41386-022-01328-y
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DOI: https://doi.org/10.1038/s41386-022-01328-y
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