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Frontal White Matter Architecture Predicts Efficacy of Deep Brain

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Frontal White Matter Architecture Predicts Efficacy of Deep Brain Coenen et al. Translational Psychiatry (2019) 9:197 https://doi.org/10.1038/s41398-019-0540-4 Translational Psychiatry ARTICLE Open Access Frontal white matter architecture predicts efficacy of deep brain stimulation in major depression Volker A. Coenen 1,2,3,4,5,ThomasE.Schlaepfer 2,4,6,7, Bettina Bewernick7,8, Hannah Kilian2,6, Christoph P. Kaller2,4,9, Horst Urbach2,9,10,MengLi1,2,11 and Marco Reisert1,2 Abstract Major depression is a frequent and severe disorder, with a combination of psycho- and pharmacotherapy most patients can be treated. However, ~20% of all patients suffering from major depressive disorder remain treatment resistant; a subgroup might be treated with deep brain stimulation (DBS). We present two trials of DBS to the superolateral medial forebrain bundle (slMFB DBS; FORESEE I and II). The goal was to identify informed features that allow to predict treatment response. Data from N = 24 patients were analyzed. Preoperative imaging including anatomical sequences (T1 and T2) and diffusion tensor imaging (DTI) magnetic resonance imaging sequences were used together with postoperative helical CT scans (for DBS electrode position). Pathway activation modeling (PAM) as well as preoperative structural imaging and morphometry was used to understand the response behavior of patients (MADRS). A left fronto-polar and partly orbitofrontal region was identified that showed increased volume in preoperative anatomical scans. Further statistical analysis shows that the volume of this “HUB-region” is predictive for later MADRS response from DBS. The HUB region connects to typical fiber pathways that have been addressed before 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; in therapeutic DBS in major depression. Left frontal volume growth might indicate intrinsic activity upon disconnection form the main emotional network. The results are significant since for the first time we found an informed feature that might allow to identify and phenotype future responders for slMFB DBS. This is a clear step into the direction of personalized treatments. Introduction The most researched targets are the subgenual cingulate Depression is a highly prevalent and disabling condition region (cg25, SCG = subgenual cingulate gyrus) and the that is associated with high rates of morbidity and mor- ventral capsule ventral striatum (VC/VS)5,6. Despite effi- tality. More than 300 million patients are affected cacy in single center trials, replication in multicentric worldwide1 and ~20–30% of these patients do not suffi- and controlled trials for these two pivotal target regions ciently respond to established treatments such as drug failed 3,4. medication and/or psychotherapy2. There is preliminary DBS of the superolateral medial forebrain bundle evidence that some of the patients who suffer from (slMFB) was proposed as a promising alternative for treatment resistant depression (TRD) might respond to patients suffering from TRD7. Small case series showed – deep brain stimulation (DBS)3,4. promising effects8 10. The scientific basis for this target region is its DBS modulation as a superior regulator of the reward system with contact to most of the regions Correspondence: Marco Reisert ([email protected]) hitherto targeted with DBS7 and its widespread connec- 1 Department of Stereotactic and Functional Neurosurgery, Freiburg University tions to reward-associated frontal lobe regions11 together Medical Center, Freiburg, Germany 2Medical Faculty, Freiburg University, Freiburg, Germany with its direct influence on the ventral tegmental area Full list of author information is available at the end of the article. © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Coenen et al. Translational Psychiatry (2019) 9:197 Page 2 of 10 (VTA) and the fact that anhedonia and hopelessness are using an 8-element phased-array head coil. The MR the most prominent symptoms of major depression12,13. imaging examination comprised an isotropic T2-weighted In our first two clinical case series 18 out of 24 TRD fast spin-echo sequence, a DTI sequence, and 2 patients responded well to DBS of the slMFB. However, as magnetization-prepared rapid gradient- echo scans. The 25% of patients did not benefit from slMFB DBS, identi- parameters were the following: fast spin-echo: repetition fication of potential biomarkers is key to further improve time (TR) = 12.650 ms, echo time (TE) = 100 ms, field of patient selection and to optimize individually tailored view (FOV) = 254 mm, matrix = 176 × 176, 120 sections, DBS. From a whole range of putative biomarkers, func- sections thickness = 1.44 mm, and acquisition time = tional analyses of networks involved in the processing of 3 minutes and 44 s. The resulting data were reconstructed stimuli emotional valence seem very promising, because to isotropic (1.44 × 1.44 × 1.44)-mm3 voxels. of their symptomatic involvement. Modern approaches for the evaluation of DBS in Diffusion tensor imaging sequence movement disorder surgery typically use normal popula- Single-shot spin-echo echo planar imaging pulse tion connectomes together with achieved electrode posi- sequence with TR = 13.188 ms, TE = 84 ms, FOV = 14–16 tions and VAT modeling . For the subgenual target 256 mm, matrix = 128 × 28, 70 sections, section thickness region, which can be silent during surgical implantation = 2 mm, number of gradient directions = 32, b-value = and acute stimulation, connectivity analyses now augment 1000 s/mm2, sensitivity encoding factor 2.9, acquisition the procedure, explain the effectiveness and might time = 7 minutes 54 s with isotropic reconstructed (2 2 2) 15–17 improve DBS outcome . mm3 voxels. In contrast, here we examine the predictive power of preoperative morphometric and structural connectivity Anatomical T1/T2 contrast data to explain postoperative response variability in TRD A T1-weighted 3-D magnetization-prepared rapid patients with slMFB DBS, based on imaging and clinical gradient-echo sequence was acquired before (structural response data from two clinical trials of slMFB DBS in information) and after (vessel visualization) contrast TRD patients (ClinicalTrials. gov: NCT01778790 & administration (gadolinium-diethylene-triamine pentaa- NCT0109526). The goal is to identify informed features = = = cetic acid) with a sensitivity encoding factor 4, TR including electrode positions, analyses of VAT ( volume 8.5 ms, TE = 3.8 ms, flip angle = 8, FOV = 256 mm, of activated tissue) and connectivity as well as structural matrix = 256 × 256, 160 sections, section thickness = anatomical imaging that might allow for an explanation 2 mm, acquisition time = 4 min 17 s. It resulted in and prediction of clinical response. reconstructed isotropic (1 × 1 × 1) mm3 voxels. All images Methods and materials were taken in axial orientation. Participants Preoperative CT Analysis of 24 patients (9 female) receiving bilateral slMFB DBS (FORESEE & FORESEE II trials; Clin- Stereotactic computed tomography (CT) scans were icalTrials. gov: NCT01778790 & NCT0109526). Experi- acquired on a 16-row multidetector scanner (Brilliance mental treatment according to tenets of the Declaration of 8000, Philips Healthcare, Best, The Netherlands) with a Helsinki, reviewed by the IRB of Bonn University Medical stereotactic frame. Parameters were as follows: tube vol- tage = 120 kV, tube current = 350 mA, collimation = Faculty. Written informed consent was obtained. = = The detailed techniques of stereotactic and tractography 16 × 0.75 mm, tube rotation time 1 s, pitch 0.942, matrix = 512 × 512, section thickness = 1.5 mm, incre- assisted slMFB DBS implantation and stimulation have = been published before18. Demographic details of the ment 1.5 mm. patients can be found in the supplementals. Response criterion for this study (and different from the clinical Postoperative CT outcome criteria and published results): = / > 50% Helical CT (within 12 hours after surgery) used the improvement in the Montgomery Asberg depression following parameters: tube voltage = 120 kV, tube cur- rating scale (MADRS) in 50% DBS-ON time. For more rent = 350 mA, collimation = 16 × 0.75 mm, tube rotation detailed clinical information about the considered cohort time = 0.75 s, pitch = 0.688, matrix = 512 × 512, section (including treatment courses and medication) we refer to thickness = 2 mm, increment = 1 mm. refs. 8,19. Human connectome project Imaging acquisition T1-weighted data from S500 release20, 2014 was used. MR imaging data were acquired on a whole-body 3T Overall, 396 subjects with Adult Self-report DSM-IV MR system (Philips Healthcare, Best, The Netherlands) by Depressive score normalized <65 were selected. Coenen et al. Translational Psychiatry (2019) 9:197 Page 3 of 10
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