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Figure.  Closer Proximity to Personalized Stimulation Targets Associated With Improved Response to Repetitive Transcranial Magnetic Stimulation Treatment for Depression
Closer Proximity to Personalized Stimulation Targets Associated With Improved Response to Repetitive Transcranial Magnetic Stimulation Treatment for Depression

A, Personalized stimulation targets were computed retrospectively for 26 individuals who previously received left-sided repetitive transcranial magnetic stimulation treatment for 3 weeks based on the F3 beam targeting method. Functional connectivity (FC) was computed between the subgenual cingulate cortex and each vertex comprising the dorsolateral prefrontal cortex using each individual’s own resting-state functional magnetic resonance imaging scan. Vertices most anticorrelated with the subgenual cingulate cortex were spatially clustered, and the center of the largest cluster was defined as the personalized target coordinate. Change in depression symptoms at 3 weeks was assessed compared with baseline using the Montgomery-Asberg Depression Rating Scale (MADRS). B, We anticipated that closer proximity between clinically applied and functional magnetic resonance imaging–personalized targets would lead to improved treatment response. This is a cartoon example only. C, Personalized stimulation targets (gray spheres) varied considerably across the spatial extent of the dorsolateral prefrontal cortex. D, Closer proximity between clinically applied and personalized targets associated with better clinical response.

Table.  Association Between Treatment Response and Proximity to Personalized and Group Average Stimulation Target Sitesa
Association Between Treatment Response and Proximity to Personalized and Group Average Stimulation Target Sitesa
1.
Fox  MD, Buckner  RL, White  MP, Greicius  MD, Pascual-Leone  A.  Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate.   Biol Psychiatry. 2012;72(7):595-603. doi:10.1016/j.biopsych.2012.04.028 PubMedGoogle ScholarCrossref
2.
Weigand  A, Horn  A, Caballero  R,  et al.  Prospective validation that subgenual connectivity predicts antidepressant efficacy of transcranial magnetic stimulation sites.   Biol Psychiatry. 2018;84(1):28-37. doi:10.1016/j.biopsych.2017.10.028 PubMedGoogle ScholarCrossref
3.
Cash  RFH, Zalesky  A, Thomson  RH, Tian  Y, Cocchi  L, Fitzgerald  PB.  Subgenual functional connectivity predicts antidepressant treatment response to transcranial magnetic stimulation: independent validation and evaluation of personalization.   Biol Psychiatry. 2019;86(2):e5-e7. doi:10.1016/j.biopsych.2018.12.002 PubMedGoogle ScholarCrossref
4.
Cash  RFH, Weigand  A, Zalesky  A,  et al.  Using brain imaging to improve spatial targeting of transcranial magnetic stimulation for depression.   Biol Psychiatry. 2020;S0006-3223(20)31668-1. doi:10.1016/j.biopsych.2020.05.033 PubMedGoogle Scholar
5.
Cash  R, Cocchi  L, Lv  J, Fitzgerald  P, Zalesky  A.  Toward state-of-the-art connectivity-guided TMS: personalization, precision & clinical response.  Paper presented at: 26th Annual Meeting of the Organization For Human Brain Mapping; June 23-July 3, 2020; virtual meeting. Accessed October 22, 2020. https://www.humanbrainmapping.org/files/2020/OHBM_2020_Virtual_Abstracts_2.pdf
6.
Fox  MD, Liu  H, Pascual-Leone  A.  Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity.   Neuroimage. 2013;66:151-160. doi:10.1016/j.neuroimage.2012.10.082 PubMedGoogle ScholarCrossref
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    2 Comments for this article
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    Improving Depression Outcomes with Functional Magnetic Resonance Imaging: Is Precise Target Site Sufficient Personalization?
    Brisa Fernandes, MD, MSc, PhD | University of Texas Health Science Center at Houston
    Precision neuromodulation is a critical and timely component of precision psychiatry (1). In this context, the article by Cash et al. (2) embodies one crucial element of precision neuromodulation, whether a fine target site personalization when administering repetitive transcranial magnetic stimulation (rTMS) can boost antidepressant outcomes. The answer appears to be 'yes.' Based on previous studies that suggested that the optimum site for rTMS is the one that possesses the strongest anticorrelation between the dorsolateral prefrontal cortex (DLPFC) and the subgenual cingulate cortex (SCC), Cash et al. (2) showed that, when the neurostimulation is applied closer to this optimum theorized site, its benefits are more substantial when it comes to ameliorating depression. However, targeting the site with the highest anticorrelation between the DLPFC and the SCC will probably not be enough for achieving truly individualized precision neuromodulation. Another element of the equation will be to determine if the site with the highest anticorrelation between the DLPFC and the SCC is indeed the optimum site for rTMS application to an individual person. Depression is not a unitary disease but a heterogeneous syndrome, and distinct subtypes of depression probably present with varying alterations at brain level. These varying alterations might require diverse treatments or, when it comes to neurostimulation, diverse brain stimulation sites corresponding to diverse underlying brain circuit selection. For instance, Drysdale et al. (3) found that people with depression and reduced connectivity in the anterior cingulate and orbitofrontal areas presented a better response to rTMS applied to the dorsomedial prefrontal cortex than those with hyperconnectivity in thalamic and frontostriatal networks. Siddiqi et al. (4) found that people with depression and a predominance of sadness and anhedonia presented a better response to rTMS when one brain circuit was stimulated and that those with a predominance of anxiety and somatic symptoms responded better to the stimulation of a distinct brain circuit, suggesting that different patterns of response are associated with different brain circuits targeted by rTMS.

    The ideal would be to select the optimum personalized circuity to be targeted at an individual level, and then fine select the optimum neurostimulation site target with the strongest alteration in fMRI and not only fine select the optimum target site of the same underlying brain circuitry in every person. The circuit connecting the DLPFC and the SCC might not be the ideal circuit for everyone; some might require the targeting of different circuits. One study found the correlation between the anticorrelation between the subgenual and the DLPFC and antidepressant response to rTMS applied to the DLPFC to be only of moderate magnitude (5), which might indirectly suggest that targeting different circuits might prove necessary in some individuals.

    Integrating these elements might prove challenging. However, incorporating these factors in future studies is essential to achieving the ultimate personalized precise neuromodulation.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Improving Depression Outcomes with Functional Magnetic Resonance Imaging: Is Precise Target Site Sufficient Personalization?
    Brisa Fernandes, MD, MSc, PhD | University of Texas Health Science Center at Houston
    Precision neuromodulation is a critical and timely component of precision psychiatry (1). In this context, the article by Cash et al. (2) embodies one crucial element of precision neuromodulation, whether a fine target site personalization when administering repetitive transcranial magnetic stimulation (rTMS) can boost antidepressant outcomes. The answer appears to be 'yes.' Based on previous studies that suggested that the optimum site for rTMS is the one that possesses the strongest anticorrelation between the dorsolateral prefrontal cortex (DLPFC) and the subgenual cingulate cortex (SCC), Cash et al. (2) showed that, when the neurostimulation is applied closer to this optimum theorized site, its benefits are more substantial when it comes to ameliorating depression. However, targeting the site with the highest anticorrelation between the DLPFC and the SCC will probably not be enough for achieving truly individualized precision neuromodulation. Another element of the equation will be to determine if the site with the highest anticorrelation between the DLPFC and the SCC is indeed the optimum site for rTMS application to an individual person. Depression is not a unitary disease but a heterogeneous syndrome, and distinct subtypes of depression probably present with varying alterations at brain level. These varying alterations might require diverse treatments or, when it comes to neurostimulation, diverse brain stimulation sites corresponding to diverse underlying brain circuit selection. For instance, Drysdale et al. (3) found that people with depression and reduced connectivity in the anterior cingulate and orbitofrontal areas presented a better response to rTMS applied to the dorsomedial prefrontal cortex than those with hyperconnectivity in thalamic and frontostriatal networks. Siddiqi et al. (4) found that people with depression and a predominance of sadness and anhedonia presented a better response to rTMS when one brain circuit was stimulated and that those with a predominance of anxiety and somatic symptoms responded better to the stimulation of a distinct brain circuit, suggesting that different patterns of response are associated with different brain circuits targeted by rTMS.

    The ideal would be to select the optimum personalized circuity to be targeted at an individual level, and then fine select the optimum neurostimulation site target with the strongest alteration in fMRI and not only fine select the optimum target site of the same underlying brain circuitry in every person. The circuit connecting the DLPFC and the SCC might not be the ideal circuit for everyone; some might require the targeting of different circuits. One study found the correlation between the anticorrelation between the subgenual and the DLPFC and antidepressant response to rTMS applied to the DLPFC to be only of moderate magnitude (5), which might indirectly suggest that targeting different circuits might prove necessary in some individuals.

    Integrating these elements might prove challenging. However, incorporating these factors in future studies is essential to achieving the ultimate personalized precise neuromodulation.



    Brisa S. Fernandes, M.D., M.Sc., Ph.D., Alexandre P. Diaz, M.D., Ph.D., Jair C. Soares, M.D., Ph.D.


    References

    (1) Fernandes BS et al. The New Field of Precision Psychiatry. BMC Med. 2017;15(1):80.
    (2) Cash RFH et al. JAMA Psychiatry. 2020.
    (3) Drysdale et al. Nat Med. 2017;23(1):28-38.
    (4) Siddiqi SH et al. Am J Psychiatry. 2020;177(5):435-446.
    (5) Weigand A et al. Biol Psychiatry. 2018;84(1):28-37
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    November 25, 2020

    Functional Magnetic Resonance Imaging–Guided Personalization of Transcranial Magnetic Stimulation Treatment for Depression

    Author Affiliations
    • 1Clinical Brain Networks Team, QIMR Berghofer, Brisbane, Queensland, Australia
    • 2Melbourne Neuropsychiatry Centre, The University of Melbourne, Victoria, Australia
    • 3Department of Biomedical Engineering, The University of Melbourne, Victoria, Australia
    • 4School of Biomedical Engineering, The University of Sydney, Camperdown, New South Wales, Australia
    • 5Epworth Centre for Innovation and Mental Health, Epworth Healthcare and the Monash University Central Clinical School, Camberwell, Victoria, Australia
    JAMA Psychiatry. 2021;78(3):337-339. doi:10.1001/jamapsychiatry.2020.3794

    Antidepressant outcomes to repetitive transcranial magnetic stimulation (rTMS) are better when stimulation is serendipitously delivered to sites of the dorsolateral prefrontal cortex (DLPFC) showing negative (anticorrelated) functional connectivity with the subgenual cingulate cortex (SGC).1-3 This suggests treatment response might be improved via prospective connectivity-guided targeting. However, DLPFC connectivity varies considerably between individuals.4 A pertinent question is whether treatment response could be improved via a single one-site-fits-all DLPFC target, representing the group average optimal site of SGC functional connectivity, or, alternatively, whether target site personalization is necessary.

    We addressed this question using recently developed methodology enabling functional magnetic resonance imaging (fMRI)–guided personalized coordinates to be computed with millimeter precision.5,6 Specifically, in a sample of individuals with major depressive disorder who previously received rTMS treatment, we tested whether proximity between the clinically applied and (1) fMRI-personalized or (2) fixed group average fMRI-guided DLPFC targets were associated with treatment response. We hypothesized that closer proximity to personalized targets would be associated with improved response.

    Methods

    Individuals with major depressive disorder underwent resting-state fMRI prior to and following rTMS, as part of a clinical trial (ACTRN12610001071011) from January 2011 to September 2015. Participants provided written consent and the protocol was approved by the Alfred Hospital, Monash University, and Swinburne University research ethics boards. Treatment comprised 3 weeks of daily (5 days per week, Monday through Friday) 10-Hz rTMS targeted to the left DLPFC (F3 beam method). Clinically applied stimulation sites were recorded for each individual and mapped to Montreal Neurological Space coordinates. Randomized clinical trial design and fMRI preprocessing are detailed elsewhere.3 Concatenated pretreatment and posttreatment fMRI scans (each 6 minutes and 40 seconds; total of 13 minutes and 20 seconds) were used to retrospectively compute personalized targets. Concatenation was justified based on the absence of significant pre-post differences in SGC-DLPFC connectivity (familywise error–corrected P>.05; FSL randomise). Connectivity was computed between the SGC and each DLPFC vertex. Vertices most anticorrelated with the SGC were spatially clustered, and the center of the largest cluster was defined as the personalized coordinate (Figure, A). Seed map methodology was applied to increase signal-to-noise ratio.6 The Euclidean distance between clinically applied and personalized targets was correlated with the percentage improvement in Montgomery-Asberg Depression Rating Scale score (3-week time point) (Figure, B). A group average target was defined as the DLPFC site of maximal anticorrelation with the SGC (Montreal Neurological Space coordinates: −41, 43, 27) using a normative connectivity map representing consensus across 2000 twenty-eight–minute resting-state scans from 1000 participants of the Human Connectome Project. Analysis began May 2019 and ended March 2020.

    Results

    Of 26 individuals with major depressive disorder, 15 (57.7%) were male, and the mean (SD) age was 44 (14) years. fMRI-personalized targets varied substantially across the spatial extent of the DLPFC (Figure, C). The median distance between personalized and actual targets was 30 mm. Closer proximity between the clinically applied and personalized targets was associated with improved treatment response (R = −0.60; P < .001; Figure, D). Importantly, this association remained significant after controlling for proximity between the clinically applied and connectivity-based group average DLPFC target (partial R = −0.54; P = .002). The association was not significant when personalized targets were substituted with established group average stimulation targets (Table).

    Stronger anticorrelation between the SGC and clinically applied targets was also associated with improved outcome (R = −0.57; P = .001). This association remained significant after controlling for connectivity derived from a normative connectivity map between the SGC and clinically applied targets (partial R = −0.43; P = .02).

    Discussion

    Clinical response to rTMS was significantly better when patients were serendipitously treated closer in proximity to personalized connectivity-guided targets. Critically, therapeutic outcome was unrelated to proximity to nonpersonalized group average stimulation targets. Thus, one-site-fits-all group average targets may insufficiently account for interindividual variation in network architecture. Conversely, fMRI acquisition and target site personalization may improve rTMS clinical efficacy. Optimal targets could alternatively be generically stimulated using less spatially specific methods (eg, deep rTMS), but their neurobiological and clinical efficacy might be compromised by concurrent stimulation of regions of positive SGC functional connectivity. Limitations include the retrospective evaluation and moderate sample size. Future prospective randomized clinical trials are warranted to assess the clinical potential of fMRI-guided personalized rTMS.

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    Article Information

    Corresponding Author: Robin F. H. Cash, PhD, Melbourne Neuropsychiatry Centre, The University of Melbourne, Victoria, Australia (robin.cash@unimelb.edu.au).

    Accepted for Publication: September 25, 2020.

    Published Online: November 25, 2020. doi:10.1001/jamapsychiatry.2020.3794

    Author Contributions: Dr Cash had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: All authors.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Cash, Zalesky.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Cash, Cocchi, Lv, Zalesky.

    Obtained funding: Zalesky.

    Administrative, technical, or material support: Cash, Cocchi, Lv.

    Supervision: Cocchi, Fitzgerald, Zalesky.

    Conflict of Interest Disclosures: Dr Fitzgerald reports a patent for a type of transcranial direct current stimulation device (10,112,056 B2) issued; has received equipment for research from MagVenture A/S, Nextsim, Neuronetics, Brainsway, Cervel Neurotech, and Medtronic; funding for research from Neuronetics; and is a founder of TMS Clinics Australia. Dr Zalesky reports grants from National Health and Medical Research Council during the conduct of the study. No other disclosures were reported.

    Funding/Support: Dr Cash is funded by the Australian Research Council (grant DE200101708) and Brain & Behaviour Research Foundation. Dr Cocchi is supported by the Australian National Health and Medical Research Council (grant APP1138711). Dr Lv was supported by the Australian National Health and Medical Research Council (grant APP1142801). Dr Zalesky was supported by the Australian National Health and Medical Research Council Senior Research Fellowship B (ID: 1136649).

    Role of the Funder/Sponsor: No funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Meeting Presentation: Part of this paper was presented in poster format at the 9th Annual Scientific Meeting of Biological Psychiatry Australia; October 28, 2019; Melbourne, Australia; and 26th Annual Meeting of the Organization for Human Brain Mapping; June 27-30, 2020; virtual.

    Additional Contributions: We thank all participants, nurses and staff involved, including Richard Thomson, PhD (Monash University), for study design; Jerome Maller, PhD (Monash University), for study design; Kate Hoy, PhD (Monash University), for randomized clinical trial design; Bernadette Fitzgibbon, PhD, (Monash University), for randomized clinical trial design; Rodney Anderson, BSc(Hons) (Monash University), for data collection; Caley Sullivan, BA/BSc(Hons) (Monash University), for data collection; Melanie Emonson, PhD (Monash University), for data collection; David Elliot, BSc(Hons) (Monash University), for clinical treatment; and Susan McQueen (Monash University), for clinical treatment.

    References
    1.
    Fox  MD, Buckner  RL, White  MP, Greicius  MD, Pascual-Leone  A.  Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate.   Biol Psychiatry. 2012;72(7):595-603. doi:10.1016/j.biopsych.2012.04.028 PubMedGoogle ScholarCrossref
    2.
    Weigand  A, Horn  A, Caballero  R,  et al.  Prospective validation that subgenual connectivity predicts antidepressant efficacy of transcranial magnetic stimulation sites.   Biol Psychiatry. 2018;84(1):28-37. doi:10.1016/j.biopsych.2017.10.028 PubMedGoogle ScholarCrossref
    3.
    Cash  RFH, Zalesky  A, Thomson  RH, Tian  Y, Cocchi  L, Fitzgerald  PB.  Subgenual functional connectivity predicts antidepressant treatment response to transcranial magnetic stimulation: independent validation and evaluation of personalization.   Biol Psychiatry. 2019;86(2):e5-e7. doi:10.1016/j.biopsych.2018.12.002 PubMedGoogle ScholarCrossref
    4.
    Cash  RFH, Weigand  A, Zalesky  A,  et al.  Using brain imaging to improve spatial targeting of transcranial magnetic stimulation for depression.   Biol Psychiatry. 2020;S0006-3223(20)31668-1. doi:10.1016/j.biopsych.2020.05.033 PubMedGoogle Scholar
    5.
    Cash  R, Cocchi  L, Lv  J, Fitzgerald  P, Zalesky  A.  Toward state-of-the-art connectivity-guided TMS: personalization, precision & clinical response.  Paper presented at: 26th Annual Meeting of the Organization For Human Brain Mapping; June 23-July 3, 2020; virtual meeting. Accessed October 22, 2020. https://www.humanbrainmapping.org/files/2020/OHBM_2020_Virtual_Abstracts_2.pdf
    6.
    Fox  MD, Liu  H, Pascual-Leone  A.  Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity.   Neuroimage. 2013;66:151-160. doi:10.1016/j.neuroimage.2012.10.082 PubMedGoogle ScholarCrossref
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