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The therapeutic potential of personalized connectivity-guided transcranial magnetic stimulation target over group-average target for depression

  • Gai Kong
    Affiliations
    Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200030, China
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  • Lijiang Wei
    Affiliations
    Beijing Normal University, State Key Laboratory of Cognitive Neuroscience and Learning, Beijing, China
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  • Jijun Wang
    Affiliations
    Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200030, China
    CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Science, PR China
    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai, PR China
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  • Chaozhe Zhu
    Correspondence
    Corresponding author. Beijing Normal University, State Key Laboratory of Cognitive Neuroscience and Learning, Beijing, China.
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    Beijing Normal University, State Key Laboratory of Cognitive Neuroscience and Learning, Beijing, China
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  • Yingying Tang
    Correspondence
    Corresponding author. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200030, China.
    Affiliations
    Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200030, China
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Open AccessPublished:August 01, 2022DOI:https://doi.org/10.1016/j.brs.2022.07.054
      Dear Editor,
      Repetitive transcranial magnetic stimulation (rTMS) has been widely used to treat the major depressive disorder (MDD) with a common target over the left dorsolateral prefrontal cortex (DLPFC) [
      • Jean-Pascal L.
      • André A.
      • Chris B.
      • H B.D.
      • Jérôme B.
      • Vincenzo D.L.
      • et al.
      Corrigendum to “Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018).
      ]. Studies have shown that the left DLPFC targets with better antidepressant efficacy were more negatively correlated with the subgenual cingulate cortex (sgACC), suggesting rTMS efficacy might be improved via functional connectivity (FC)-guided targeting [
      • Fox M.D.
      • Buckner R.L.
      • White M.P.
      • Greicius M.D.
      • Pascual-Leone A.
      Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate.
      ,
      • Weigand A.
      • Horn A.
      • Caballero R.
      • Cooke D.
      • Stern A.P.
      • Taylor S.F.
      • et al.
      Prospective validation that subgenual connectivity predicts antidepressant efficacy of transcranial magnetic stimulation sites.
      ,
      • Cash R.F.H.
      • Zalesky A.
      • Thomson R.H.
      • Tian Y.
      • Cocchi L.
      • Fitzgerald P.B.
      Subgenual functional connectivity predicts antidepressant treatment response to transcranial magnetic stimulation: independent validation and evaluation of personalization.
      ]. A multi-site rTMS study using the group-average DLPFC target, defined as the most negative FC with sgACC from a cohort of healthy controls, reported a high response rate of 49% in MDD [
      • Blumberger D.M.
      • Vila-Rodriguez F.
      • Thorpe K.E.
      • Feffer K.
      • Noda Y.
      • Giacobbe P.
      • et al.
      Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.
      ]. Establishing a group-level DLPFC target has the advantages of being robust and minimizing noise effects but ignoring the individual variability in sgACC-DLPFC functional connectivity [
      • Fox M.D.
      • Liu H.
      • Pascual-Leone A.
      Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity.
      ]. Some studies have proposed that the personalized DLPFC targets, defined as the individual maximal sgACC-DLPFC functional connectivity, may bring a better efficacy than the group-average DLPFC target [
      • Fox M.D.
      • Liu H.
      • Pascual-Leone A.
      Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity.
      ,
      • Cash R.F.H.
      • Cocchi L.
      • Lv J.
      • Wu Y.
      • Fitzgerald P.B.
      • Zalesky A.
      Personalized connectivity-guided DLPFC-TMS for depression: advancing computational feasibility, precision and reproducibility.
      ]. Stanford Neuromodulation Therapy demonstrated a high remission rate of 79% by using personalized DLPFC targets and an accelerated, high-dose protocol [
      • Cole E.J.
      • Phillips A.L.
      • Bentzley B.S.
      • Stimpson K.H.
      • Nejad R.
      • Barmak F.
      • et al.
      Stanford neuromodulation Therapy (snt): a double-blind randomized controlled trial.
      ]. However, whether rTMS with personalized DLPFC targets has the therapeutic advantage over the group-average target for depression remains unclear in the lack of direct comparisons between antidepressant outcomes from these two targeting methods.
      Two retrospective studies provided an alternative way to examine the therapeutic potential of personalized DLFPC targets relative to other targeting methods [
      • Cash R.F.H.
      • Cocchi L.
      • Lv J.
      • Fitzgerald P.B.
      • Zalesky A.
      Functional magnetic resonance imaging–guided personalization of transcranial magnetic stimulation treatment for depression.
      ,
      • Siddiqi S.H.
      • Weigand A.
      • Pascual-Leone A.
      • Fox M.D.
      Identification of personalized transcranial magnetic stimulation targets based on subgenual cingulate connectivity: an independent replication.
      ]. By calculating the Euclidean distances between the actual targets from the ‘Beam F3′ method [
      • Cash R.F.H.
      • Cocchi L.
      • Lv J.
      • Fitzgerald P.B.
      • Zalesky A.
      Functional magnetic resonance imaging–guided personalization of transcranial magnetic stimulation treatment for depression.
      ] and the ‘5.5 cm’ method [
      • Siddiqi S.H.
      • Weigand A.
      • Pascual-Leone A.
      • Fox M.D.
      Identification of personalized transcranial magnetic stimulation targets based on subgenual cingulate connectivity: an independent replication.
      ] and personalized DLPFC targets, they found a better antidepressant outcome with a closer distance to the personalized target, suggesting the therapeutic potential of personalized DLPFC targets relative to the two conventional targeting methods. In our MDD patients who received rTMS previously over the group-average DLPFC site, we followed the same logic to investigate the therapeutic potential of personalized DLPFC targets relative to the group-average target. We hypothesized that closer proximity between group-average and personalized targets would be associated with better antidepressant outcomes.
      The present study recruited 18 MDD outpatients between January 2018 and March 2021 at Shanghai Mental health Center (SHMC). The institutional ethical board of SMHC approved the protocol (2017–43), and all participants provided written consent before study entry. They all received 10-Hz rTMS treatment every weekday, amounting to 20 sessions. A common precise DLPFC target (Montreal Neurological Space coordinates: −42, 44, 30) was used with a group-average maximal sgACC-DLPFC connectivity [
      • Weigand A.
      • Horn A.
      • Caballero R.
      • Cooke D.
      • Stern A.P.
      • Taylor S.F.
      • et al.
      Prospective validation that subgenual connectivity predicts antidepressant efficacy of transcranial magnetic stimulation sites.
      ]. The target was localized using individual structural MRI data guided by the Localite Neuronavigation System (NDI, Canada). All patients completed the Montgomery-Asberg Depression Rating Scale (MADRS) assessments, structural magnetic resonance imaging (MRI), and resting-state functional MRI acquisitions before and after 20-session rTMS treatment. MRI data were collected from a 3.0 T Siemens Verio MRI scanner (MRB17, Siemens AG, Erlangen, Germany) in SMHC (detailed parameters in supplementary materials). Functional connectivity was computed between each voxel within the left DLFPC and a sgACC-based seed map which substituted sgACC to improve the signal-to-noise ratio [
      • Fox M.D.
      • Liu H.
      • Pascual-Leone A.
      Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity.
      ]. The personalized DLPFC target was identified by the sphere's center with a radius of 9 mm with a maximum of negative FC values. The Euclidean distance between group-average DLPFC target and personalized DLPFC targets was calculated, while the correlation of the distance and percentage improvement in MARDS score by rTMS was examined.
      Of 18 MDD patients, 11 (61%) were female, the mean (SD) age was 31 (6) years old. The mean (SD) percentage of improvements in MARDS score was 75% (20%). Closer proximity between the group-average and personalized targets was significantly correlated with better MADRS improvements (R = −0.554; P = 0.017) (Fig. 1A). According to the fitted line, the mean percentage of improvement in MARDS score would be 89% if all depressive patients received rTMS over personalized targets (Fig. 1A). Compared to the actual group-average target, target site personalization further took a 14% increase in MADRS improvements theoretically. The response rate was 100% (n = 14 of 14) for patients when the distance to the group-average target was closer than 29 mm. The response rate was 25% (n = 1 of 4) for the remaining patients whose personalized targets were far away from the group-average target (Fig. 1B).
      Fig. 1
      Fig. 1(A) Closer proximity between the group-average target and personalized target was associated with improved treatment response. (B) Patients (N = 18) received the rTMS treatment over the common group-average target (yellow dot). Personalized sgACC-DLPFC targets were retrospectively computed and depicted by the red dots (responders) or the blue dots (nonresponders). MADRS, Montgomery-Asberg Depression Rating Scale; sgACC, the subgenual cingulate cortex; DLPFC, the dorsolateral prefrontal cortex. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
      In general, MDD patients showed better antidepressant improvements when the actual group-average target was closer to the personalized target. Our results suggested that target site personalization indicates a degree of potential therapeutic benefits for MDD even over the group-average target. Limitations of the present study include the retrospective evaluation and moderate sample size.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      This work was supported by National Nature Science Foundation of China ( 81871050 , 81971251 ); Natural Science Foundation of Shanghai ( 17ZR1424700 , 21ZR1481500 ); Key Projects of Shanghai Clinical Research Center ( CRC2018ZD01 , CRC2019ZD02 ); Shanghai Clinical Research Center for Mental Health ( 19MC1911100 ); Project of the Key Discipline Construction , Shanghai 3-Year Public Health Action Plan ( GWV-10.1-XK18 ). Yingying Tang is funded by Shanghai Municipal Education Commission— Gaofeng Clinical Medicine Grant Support ( 20191836 ).

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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