Deborah C.W. Klooster, PhD; Iris N. Vos, BSc; Karen Caeyenberghs, PhD; Alexander Leemans, PhD; Szabolcs David, PhD; René M.H. Besseling, PhD; Albert P. Aldenkamp, PhD; Chris Baeken, MD, PhD
Background: Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD), but its clinical efficacy remains rather modest. One reason for this could be that the propagation of rTMS effects via structural connections from the stimulated area to deeper brain structures (such as the cingulate cortices) is suboptimal.
Methods: We investigated whether structural connectivity — derived from diffusion MRI data — could serve as a biomarker to predict treatment response. We hypothesized that stronger structural connections between the patient-specific stimulation position in the left dorsolateral prefrontal cortex (dlPFC) and the cingulate cortices would predict better clinical outcomes. We applied accelerated intermittent theta burst stimulation (aiTBS) to the left dlPFC in 40 patients with MDD. We correlated baseline structural connectivity, quantified using various metrics (fractional anisotropy, mean diffusivity, tract density, tract volume and number of tracts), with changes in depression severity scores after aiTBS.
Results: Exploratory results (p < 0.05) showed that structural connectivity between the patient-specific stimulation site and the caudal and posterior parts of the cingulate cortex had predictive potential for clinical response to aiTBS.
Limitations: We used the diffusion tensor to perform tractography. A main limitation was that multiple fibre directions within voxels could not be resolved, which might have led to missing connections in some patients.
Conclusion: Stronger structural frontocingular connections may be of essence to optimally benefit from left dlPFC rTMS treatment in MDD. Even though the results are promising, further investigation with larger numbers of patients, more advanced tractography algorithms and classic daily rTMS treatment paradigms is warranted.
Clinical trial registration: http://clinicaltrials.gov/show/NCT01832805
Submitted Apr. 30, 2019; Revised July 23, 2019; Accepted Aug. 27, 2019; Published online Jan. 28, 2020
Acknowledgements: D. Klooster and C. Baeken are supported by the Ghent University Multidisciplinary Research Partnership, “The integrative neuroscience of behavioral control,” and a grant of the “Fonds Wetenschappelijk Onderzoek Rode Neuzen” (G0F4617N). K. Caeyenberghs is supported by a Career Development Fellowship from the National Health and Medical Research Council and an ACURF Program grant from the Australian Catholic University. The research of S. David and A. Leemans is supported by VIDI Grant 639.072.411 from the Netherlands Organization for Scientific Research (NWO).
Affiliations: From the Eindhoven University of Technology, Department of Electrical Engineering, Eindhoven, the Netherlands (Klooster, Vos, Besseling, Aldenkamp); the Academic Center for Epileptology Kempenhaeghe, Department of Research and Development, Heeze, the Netherlands (Klooster, Aldenkamp); Ghent University, Ghent Experimental Psychiatry Laboratory, Ghent, Belgium (Baeken); the Australian Catholic University, Faculty of Health Sciences, Mary MacKillop Institute for Health Research, Melbourne, Australia (Caeyenberghs); the PROVIDI Lab, Image Sciences Institute, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands (Leemans, David); the Brussel University Hospital, Department of Psychiatry, Brussels, Belgium (Baeken).
Competing interests: None declared.
Contributors: D. Klooster, R. Besseling, A. Aldenkamp and C. Baeken designed the study. C. Baeken acquired and analyzed the data, which D. Klooster, I. Vos, K. Caeyenberghs, A. Leemans and S. David also analyzed. D. Klooster and C. Baeken wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Correspondence to: D.C.W. Klooster, Eindhoven University of Technology, Department of Electrical Engineering, Building Flux, Office 5.084, De Groene Loper 19, 5612 AZ Eindhoven, the Netherlands; firstname.lastname@example.org