Blomstedt, Patric

Coenen, Volker A.

Fenoy, Albert J.

Hariz, Marwan

Reinacher, Peter C.

Schlaepfer, Thomas E.

Schuurman, P. Rick

Varkuti, Balint

Voges, Juergen

Zrinzo, Ludvic

NARCIS 

Surgical decision making for deep brain stimulation should not be based on aggregated normative data mining

Coenen, VA

Schlaepfer, TE

Varkuti, B

Schuurman, PR

Reinacher, PC

Voges, J

Zrinzo, L

Blomstedt, P

Fenoy, AJ

Hariz, M

UCL Discovery

lable at ScienceDirectBrain Stimulation xxx (xxxx) xxxContents lists avaiBrain Stimulationjournal homepage: http : / /www.journals .elsevier .com/brain-st imulat ionSurgical decision making for deep brain stimulation should not bebased on aggregated normative data miningKeywords:Deep Brain StimulationDBSnormative datapreprint publishingdata aggregationDiffusion Tensor ImagingConnectomic surgerymedial forebrain bundleOCDObsessive compulsive disorderhttps://doi.org/10.1016/j.brs.2019.07.0141935-861X/© 2019 The Authors. Published by ElsevierPlease cite this article as: Coenen VA et al., Sdata mining, Brain Stimulation, https://doi.othe driveitant OCDWe read with interest the manuscript by Li et al. “Toward a uni-ﬁed connectomic target for deep brain stimulation in obsessive-compulsive disorder”, published on the preprint server bioRxiv (13april 2019) [18]. We would like to comment on the far-reachingconclusions drawn from the use of aggregated normative and con-nectomic data for their impact on decision making for surgical tar-geting in deep brain stimulation (DBS). Furthermore, wewould liketo discuss the emerging use of publication of unreviewed scientiﬁcdata in various open formats.In their work, Li et al. compare two different patient cohortsundergoing DBS for treatment resistant obsessive compulsivedisorder (OCD) from two study centers, Grenoble (n¼ 14) andCologne (n¼ 22) with DBS in two different brain targets, theanteromedial subthalamic nucleus (amSTN) in Grenoble and theanterior limb of the internal capsule¼ ALIC in Cologne. The re-sults of the Cologne cohort have previously been published in avery similar context, somewhat surprisingly with different re-sults [5,18]. Li et al. base their conclusion on the analysis of aggre-gated normative data (due to a lack of individual tractographicdata in both cohorts), assuming by this that these patients haveunaltered, identical white matter anatomy. They ﬁnd a common“tract target” that jointly explains anti OCD effects in bothgroups, and they conclude that this new pathway might be offurther use in DBS. These results are certainly relevant - albeitnot new [9,19].The article implies that the associative/limbic parts of the STNwere targeted by DBS for OCD because of image derived circuitryand connectivity. Although the imaging data are highly interestingfrom a mechanistic viewpoint, the reality is that serendipity wasInc. This is an open access article uurgical decision making for drg/10.1016/j.brs.2019.07.014r, after case reports emerged of improvement in concom-symptoms in patients who had undergone STN DBS forParkinson's disease [15,20].Li et al. state: […] “This ﬁnal bundle may indeed represent a“tract-target” to treat OCD with DBS. Given this potential clinicalimportance, we characterized its anatomical properties using addi-tional views relatively to anatomical landmarks that could be usedduring stereotactic planning [ …]”. [18] This is probably the mostproblematic sentence in this paper as it points to the use ofnormative data for DBS surgical planning. Neurosurgeons havemoved away from normative atlases and embraced the evolutionof structural MRI in stereotactic surgery (allowing direct target-ing); more recently tractographic methods are being investigatedfor direct targeting [12,23]. Whatever the imaging technology,surgical targeting and planning are based on imaging from theindividual who is undergoing surgery. The normative aggregatedlarge cohort data approach recently offered by Horn et al. to theDBS ﬁeld [16,17] can be very useful when exploring group data,but becomes problematic when it claims to guide DBS surgeryin individual patients: the anatomy of large normative cohorts(n) are morphed into a uniﬁed space (MNI¼Montreal Neurolog-ical Institute space) which thereby becomes an atlas, not betterand probably even worse than the histological atlases based onthe mid-commissural point, “augmented” with normative largecohort connectomic information (e.g. human connectome project[18]). It cannot support conclusions on where an effective elec-trode should ideally be placed in individual patients consideringnormal anatomical variations and potentially disease-related al-terations of (white matter) anatomy. It is of note that the scien-tiﬁc ﬁeld perceives this augmentation with normative data andits aggregation as a step towards individualized target deﬁnitionfor DBS in psychiatric diseases [26]. In a stricter and stereotacticsense, it is not. Even papers using high quality patient individualconnectome data to analyze lead location as a function of clinicaloutcome in the better understood neural pathways involved intremor are more cautious when considering extrapolation ofthis approach prospectively in patients [1].Open source systems such as Lead-DBS [16] are not CE or FDAapproved and they are not tools intended and cleared for patienttreatment (including both surgical planning and neurological pro-gramming) but they can be perceived and used as such. These sys-tems characterize as research tools and are used to aggregate datafrom different sources (and in part from undisclosed, often chang-ing libraries) to analyze and draw conclusions on “optimal”nder the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).eep brain stimulation should not be based on aggregated normativeFig. 1. MFB. A, cropped image from Li et al. showing the “tract target” atlas. B, taken from Ref. [9], showing the slMFB.V.A. Coenen et al. / Brain Stimulation xxx (xxxx) xxx2electrode positions, and by this, on targeting. While this is stated indisclaimers, the message is that new generations of DBS clinician-scientists are offered the use of normative information to placeelectrodes and “test” new targets which they perceive as reality.Although in our opinion it can be useful to work with normativedata for pure analysis, it is problematic if normative informationis to be used for targeting in a real patient who is not part of theanalyzed cohort (the n þ 1 patient). The use of aggregated patientcohorts is an alternative [1] that can inform targeting that mustbe based on individual imaging [21]. Until prospectively acquireddata have demonstrated the superiority of targeting on the basisof new forms of normative data (beyond the traditional MCP(¼midcommissural point) “libraries”) with regards to safety andclinical outcomes, authors should temper conclusions based onretrospective data collection with respect to the complex clinical-surgical decision process. A better example for trial design is theactual comparison of the two target regions (ALIC, amSTN) in a pro-spective blinded clinical study with a crossover design and analysisof individual connectomic data, published recently [25]. The realitytoday remains, that targeting decisions are an amalgamation ofdirect imaging of visualized structures, implicit or explicit use ofnormative data, possible intraoperative testing in the awake pa-tient, and immediate postoperative imaging for conﬁrmation oflead location and targeting accuracy.The scientiﬁc community should also be alerted to the prolifer-ation of preprint publishing sites. Websites that present un-reviewed data include the bioRxiv service, the “Lead-DBS” home-page (linked), Research gate and other social media, as well asopen digital libraries [16] that in the future might contain norma-tively derived brain structures.The bioRxiv homepage states: “Before formal publication in a schol-arly journal, scientiﬁc and medical articles are traditionally “peerreviewed.” […] “Readers should therefore be aware that articles onbioRxiv have not been ﬁnalized by authors, might contain errors,and report information that has not yet been accepted or endorsedin any way by the scientiﬁc or medical community.” [for full state-ment cf: Anonymous (2019) https://www.biorxiv.org/content/what-unrefereed-preprint, assessed 26 april 2019].It is not always easy to differentiate a self-published and unre-viewed preprint from an already reviewed and accepted manu-script preprint. However, this form of unreviewed preprintpublishing obviously is in concordance with publication politicsof at least some Journals. [Anonymous (2017) Preprints under re-view. nature communications. https://www.nature.com/articles/Please cite this article as: Coenen VA et al., Surgical decision making for ddata mining, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.07.014s41467-017-00950-5.pdf (accessed online 26 april 2019)]. Under-standing the nature of preprint data publishing is important forthe evaluation of scientiﬁc data and the above-mentioneddisclaimer is helpful. Moreover, in this instance there is a poten-tially dangerous combination where unreviewed scientiﬁc dataare made available to the DBS community, open for uncritical usein uncontrolled and unregulated open source planning and visual-ization environments [16].Li et al. state: […] “Finally, we show that most if not all literature-deﬁned DBS targets that were used to treat OCD in the past fall alongthe tract-target identiﬁed in the present study”. [18] This pathway haspreviously been published as a target for DBS in major depression[23] and OCD [9,19]. It was anatomically characterized[3,7,8,10,11,22,27] (Fig. 1, right) together with a scientiﬁc frame-work, including its relation to other target regions for OCD and ma-jor depression (ALIC, NAC¼ Nucleus Accumbens, amSTN) [9e11,24](Fig. 2). More than 50 patients have already undergone DBS to thisﬁber pathway using individual connectomic imaging for targetingacross both indications and 30 patients are already published[6,13,23].For OCD we fear that a potential next step will be: The pathwayin question will live in a digital open source library [16] as a “tracttarget” atlas (in MNI space) andmight be used for individual target-ing. Recent literature [4,6,12e14,23] is suggestive of a potential(and plausible) superiority of exclusive direct imaging as an indi-vidualized targeting rationale. With respect to this literature it isimportant to remember that the approaches mentioned by Liet al. [18] have never been contrasted in a direct prospective com-parison format. While retrospective analysis (including the use ofnormative data) can inform future research directions, surgical de-cision making in centers around the world still remains a non-standardized and expertise-driven affair. Until robust data to thecontrary becomes available, anatomical information (structuraland connectivity data) used for stereotactic surgery should be indi-vidual, identiﬁed in a scientiﬁc and anatomical framework, person-alized and of determined accuracy, with full understanding of thepitfalls and limitations of the technique [2,28]. As scientiﬁc infor-mation can now be widely available in fully un-reviewed formatsover preprint servers, social media and free digital libraries, scien-tists should be cautious with such publication strategies since thesemay result in inappropriate use of their un-reviewed data. This isespecially important in the ﬁeld of medicine and even more so insurgical decision-making.eep brain stimulation should not be based on aggregated normativeFig. 2. A, Surgical targets related to the “tract target” taken from Li et al. [18]. B, the slMFB taken from Ref. [11]. C, surgical targets for OCD (yellow) related to the slMFB (dark green)taken from Ref. [9]. The anterior thalamic radiation (ATR, orange) which runs parallel to slMFB in ALIC might in part explain the diverging results from the previous publication [5].V.A. Coenen et al. / Brain Stimulation xxx (xxxx) xxx 3References[1] Akram H, Dayal V, Mahlknecht P, et al. Connectivity derived thalamic segmen-tation in deep brain stimulation for tremor. Neuroimage: Neuroimage Clin2018;18:130e42.[2] Akram H, Hariz M, Zrinzo L. Connectivity derived thalamic segmentation_Separating myth from reality. Neuroimage: Neuroimage Clin 2019:101758.[3] Anthofer JM, Steib K, Fellner C, Lange M, Brawanski A, Schlaier J. DTI-baseddeterministic ﬁbre tracking of the medial forebrain bundle. Acta Neurochir2015;157(3):469e77.[4] Aviles-Olmos I, Kefalopoulou Z, Tripoliti E, et al. Long-term outcome of sub-thalamic nucleus deep brain stimulation for Parkinson's disease using anMRI-guided and MRI-veriﬁed approach. J Neurol Neurosurg Psychiatry2014;85(12):1419e25.[5] Baldermann JC, Melzer C, Zapf A, et al. 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A randomized trial directlycomparing ventral capsule and anteromedial subthalamic nucleus stimulationin obsessive-compulsive disorder: clinical and imaging evidence for disso-ciable effects. Biol Psychiatry 2019;85(9):726e34.[26] Voon V. Toward precision medicine: prediction of deep brain stimulation tar-gets of the ventral internal capsule for obsessive-compulsive disorder. BiolPsychiatry 2019;85(9):708e10.[27] Zacharopoulos G, Lancaster TM, Bracht T, Ihssen N, Maio GR, Linden DEJ. A he-donism hub in the human brain. Cerebr Cortex 2016;26(10):3921e7.[28] Zrinzo L. Pitfalls in precision stereotactic surgery. Surg Neurol Int 32012;(Suppl 1). S53e61.Volker A. Coenen*Department of Stereotactic and Functional Neurosurgery, FreiburgUniversity Medical Center, Medical Faculty of Freiburg University,GermanyPlease cite this article as: Coenen VA et al., Surgical decision making for ddata mining, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.07.014Center for Basics in Neuromodulation, Freiburg University, GermanyThomas E. SchlaepferDepartment of Interventional Biological Psychiatry, FreiburgUniversity Medical Center, Medical Faculty of Freiburg University,GermanyBalint VarkutiCortics, Munich, GermanyP. Rick SchuurmanAmsterdam UMC, University of Amsterdam, Department ofNeurosurgery, Amsterdam Neuroscience, Meibergdreef 9, 1105, AZ,Amsterdam, the NetherlandsPeter C. ReinacherDepartment of Stereotactic and Functional Neurosurgery, FreiburgUniversity Medical Center, Medical Faculty of Freiburg University,GermanyJuergen VogesDepartment of Stereotactic Neurosurgery, Otto von GuerickeUniversity, Magdeburg, GermanyLudvic ZrinzoFunctional Neurosurgery Unit, UCL Queen Square Institute ofNeurology, London, UKPatric BlomstedtDepartment of Clinical Neuroscience, University Hospital, 90185,Umeå, SwedenAlbert J. FenoyDepartment of Neurosurgery, McGovern Medical School, University ofTexas, Houston, USAMarwan HarizDepartment of Clinical Neuroscience, University Hospital, 90185,Umeå, Sweden* Corresponding author.E-mail address: volker.coenen@uniklinik-freiburg.de (V.A. Coenen).6 May 2019Available online xxxeep brain stimulation should not be based on aggregated normative

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Surgical decision making for deep brain stimulation should not be based on aggregated normative data mining

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