Association of Repetitive Transcranial Magnetic Stimulation Treatment With Subgenual Cingulate Hyperactivity in Patients With Major Depressive Disorder: A Secondary Analysis of a Randomized Clinical Trial

Itay Hadas, Yinming Sun, Pantelis Lioumis, Reza Zomorrodi, Brett Jones, Daphne Voineskos, Jonathan Downar, Paul B. Fitzgerald, Daniel M. Blumberger, Zafiris J. Daskalakis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Importance: Hyperactivity in the subgenual cingulate cortex (SGC) is associated with major depressive disorder (MDD) and anticorrelated with activity in the dorsolateral prefrontal cortex (DLPFC). This association was found to be predictive of responsiveness to repetitive transcranial magnetic stimulation (rTMS) treatment. Such findings suggest that DLPFC-SGC connectivity is important for understanding both the therapeutic mechanism of rTMS in patients with MDD and the underlying pathophysiology of MDD. Objective: To evaluate SGC hyperactivity in patients with MDD before and after rTMS treatment. Design, Setting, and Participants: In this diagnostic study, among participants recruited from the adult and geriatric mood and anxiety services at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, who had participated in a randomized clinical trial, baseline SGC activity of patients with MDD was compared with healthy controls. In patients with MDD, SGC activity was compared before and after active or sham high-frequency rTMS treatment. Data collection started in July 2008 and concluded in March 2012. Neurophysiological data analysis started in January 2017 and ended in May 2018. Main Outcomes and Measures: Hyperactivity in the SGC before and after rTMS treatment was measured. Subgenual cingulate cortex hyperactivity activity was quantified using significant current density (SCD), and effective connectivity between the left DLPFC and SGC was computed using significant current scattering (SCS). Both measures were computed around TMS evoked potentials standard peak latencies prior to rTMS and after rTMS treatment, comparing patients with MMD treated with active and sham rTMS. Patients with MDD were assessed with the 17-item Hamilton Rating Scale for Depression. Results: Of 121 patients with MDD in the initial trial, 30 (15 [50.0%] women) were compared with 30 healthy controls (15 [50.0%] women) at rTMS treatment baseline. The mean (SD) age of the cohort with MDD was 39.1 (10.9) years, and the mean (SD) age of healthy controls was 37.0 (11.0) years. Following rTMS treatment, 26 patients with MDD who had active rTMS treatment (21.5%) were compared with 17 patients with MDD who had sham treatment (14.0%). At baseline, the SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after TMS pulse were higher in participants with MDD compared with healthy controls (SCD: 1.04 × 10-6 [1.41 × 10-6] μA/mm2 vs 3.8 × 10-7 [7.8 × 10-7] μA/mm2; z = -2.95; P = .004; SCS: 0.87 [0.86] mm vs 0.54 [0.87] mm; z = -2.27; P = .02). Baseline source current density was able to classify MDD with 77% accuracy. Scores on the 17-item Hamilton Rating Scale for Depression were correlated with current density at the SGC (ρ = 0.41; P = .03). After rTMS treatment, SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after rTMS pulse were attenuated to approximately the standard TMS-evoked potential latencies in the active rTMS group compared with the sham rTMS group (SCD: 1.57 × 10-7 [3.67 × 10-7] μA/mm2 vs 7.00 × 10-7 [7.51 × 10-7] μA/mm2; z = -2.91; P = .004; SCS: 0.20 [0.44] mm vs 0.74 [0.73] mm; z = -2.78; P = .006). Additionally, the SGC SCS change was correlated with symptom improvement on the 17-item Hamilton Rating Scale for Depression in the active rTMS group (ρ = 0.58; P = .047). Conclusions and Relevance: The findings of this study further implicate left DLPFC-SGC effective connectivity and SGC excitability in the pathophysiology of MDD and treatment with rTMS. These findings suggest that DLPFC-SGC connectivity may be a marker of rTMS treatment responsiveness. Trial Registration: ClinicalTrials.gov identifier: NCT01515215.

Original languageEnglish
Article numbere195578
Number of pages13
JournalJAMA network open
Volume2
Issue number6
DOIs
Publication statusPublished - 5 Jun 2019

Cite this

Hadas, Itay ; Sun, Yinming ; Lioumis, Pantelis ; Zomorrodi, Reza ; Jones, Brett ; Voineskos, Daphne ; Downar, Jonathan ; Fitzgerald, Paul B. ; Blumberger, Daniel M. ; Daskalakis, Zafiris J. / Association of Repetitive Transcranial Magnetic Stimulation Treatment With Subgenual Cingulate Hyperactivity in Patients With Major Depressive Disorder : A Secondary Analysis of a Randomized Clinical Trial. In: JAMA network open. 2019 ; Vol. 2, No. 6.
@article{107636826601407eb2654181d48ec660,
title = "Association of Repetitive Transcranial Magnetic Stimulation Treatment With Subgenual Cingulate Hyperactivity in Patients With Major Depressive Disorder: A Secondary Analysis of a Randomized Clinical Trial",
abstract = "Importance: Hyperactivity in the subgenual cingulate cortex (SGC) is associated with major depressive disorder (MDD) and anticorrelated with activity in the dorsolateral prefrontal cortex (DLPFC). This association was found to be predictive of responsiveness to repetitive transcranial magnetic stimulation (rTMS) treatment. Such findings suggest that DLPFC-SGC connectivity is important for understanding both the therapeutic mechanism of rTMS in patients with MDD and the underlying pathophysiology of MDD. Objective: To evaluate SGC hyperactivity in patients with MDD before and after rTMS treatment. Design, Setting, and Participants: In this diagnostic study, among participants recruited from the adult and geriatric mood and anxiety services at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, who had participated in a randomized clinical trial, baseline SGC activity of patients with MDD was compared with healthy controls. In patients with MDD, SGC activity was compared before and after active or sham high-frequency rTMS treatment. Data collection started in July 2008 and concluded in March 2012. Neurophysiological data analysis started in January 2017 and ended in May 2018. Main Outcomes and Measures: Hyperactivity in the SGC before and after rTMS treatment was measured. Subgenual cingulate cortex hyperactivity activity was quantified using significant current density (SCD), and effective connectivity between the left DLPFC and SGC was computed using significant current scattering (SCS). Both measures were computed around TMS evoked potentials standard peak latencies prior to rTMS and after rTMS treatment, comparing patients with MMD treated with active and sham rTMS. Patients with MDD were assessed with the 17-item Hamilton Rating Scale for Depression. Results: Of 121 patients with MDD in the initial trial, 30 (15 [50.0{\%}] women) were compared with 30 healthy controls (15 [50.0{\%}] women) at rTMS treatment baseline. The mean (SD) age of the cohort with MDD was 39.1 (10.9) years, and the mean (SD) age of healthy controls was 37.0 (11.0) years. Following rTMS treatment, 26 patients with MDD who had active rTMS treatment (21.5{\%}) were compared with 17 patients with MDD who had sham treatment (14.0{\%}). At baseline, the SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after TMS pulse were higher in participants with MDD compared with healthy controls (SCD: 1.04 × 10-6 [1.41 × 10-6] μA/mm2 vs 3.8 × 10-7 [7.8 × 10-7] μA/mm2; z = -2.95; P = .004; SCS: 0.87 [0.86] mm vs 0.54 [0.87] mm; z = -2.27; P = .02). Baseline source current density was able to classify MDD with 77{\%} accuracy. Scores on the 17-item Hamilton Rating Scale for Depression were correlated with current density at the SGC (ρ = 0.41; P = .03). After rTMS treatment, SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after rTMS pulse were attenuated to approximately the standard TMS-evoked potential latencies in the active rTMS group compared with the sham rTMS group (SCD: 1.57 × 10-7 [3.67 × 10-7] μA/mm2 vs 7.00 × 10-7 [7.51 × 10-7] μA/mm2; z = -2.91; P = .004; SCS: 0.20 [0.44] mm vs 0.74 [0.73] mm; z = -2.78; P = .006). Additionally, the SGC SCS change was correlated with symptom improvement on the 17-item Hamilton Rating Scale for Depression in the active rTMS group (ρ = 0.58; P = .047). Conclusions and Relevance: The findings of this study further implicate left DLPFC-SGC effective connectivity and SGC excitability in the pathophysiology of MDD and treatment with rTMS. These findings suggest that DLPFC-SGC connectivity may be a marker of rTMS treatment responsiveness. Trial Registration: ClinicalTrials.gov identifier: NCT01515215.",
author = "Itay Hadas and Yinming Sun and Pantelis Lioumis and Reza Zomorrodi and Brett Jones and Daphne Voineskos and Jonathan Downar and Fitzgerald, {Paul B.} and Blumberger, {Daniel M.} and Daskalakis, {Zafiris J.}",
year = "2019",
month = "6",
day = "5",
doi = "10.1001/jamanetworkopen.2019.5578",
language = "English",
volume = "2",
journal = "JAMA network open",
issn = "2574-3805",
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Association of Repetitive Transcranial Magnetic Stimulation Treatment With Subgenual Cingulate Hyperactivity in Patients With Major Depressive Disorder : A Secondary Analysis of a Randomized Clinical Trial. / Hadas, Itay; Sun, Yinming; Lioumis, Pantelis; Zomorrodi, Reza; Jones, Brett; Voineskos, Daphne; Downar, Jonathan; Fitzgerald, Paul B.; Blumberger, Daniel M.; Daskalakis, Zafiris J.

In: JAMA network open, Vol. 2, No. 6, e195578, 05.06.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Association of Repetitive Transcranial Magnetic Stimulation Treatment With Subgenual Cingulate Hyperactivity in Patients With Major Depressive Disorder

T2 - A Secondary Analysis of a Randomized Clinical Trial

AU - Hadas, Itay

AU - Sun, Yinming

AU - Lioumis, Pantelis

AU - Zomorrodi, Reza

AU - Jones, Brett

AU - Voineskos, Daphne

AU - Downar, Jonathan

AU - Fitzgerald, Paul B.

AU - Blumberger, Daniel M.

AU - Daskalakis, Zafiris J.

PY - 2019/6/5

Y1 - 2019/6/5

N2 - Importance: Hyperactivity in the subgenual cingulate cortex (SGC) is associated with major depressive disorder (MDD) and anticorrelated with activity in the dorsolateral prefrontal cortex (DLPFC). This association was found to be predictive of responsiveness to repetitive transcranial magnetic stimulation (rTMS) treatment. Such findings suggest that DLPFC-SGC connectivity is important for understanding both the therapeutic mechanism of rTMS in patients with MDD and the underlying pathophysiology of MDD. Objective: To evaluate SGC hyperactivity in patients with MDD before and after rTMS treatment. Design, Setting, and Participants: In this diagnostic study, among participants recruited from the adult and geriatric mood and anxiety services at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, who had participated in a randomized clinical trial, baseline SGC activity of patients with MDD was compared with healthy controls. In patients with MDD, SGC activity was compared before and after active or sham high-frequency rTMS treatment. Data collection started in July 2008 and concluded in March 2012. Neurophysiological data analysis started in January 2017 and ended in May 2018. Main Outcomes and Measures: Hyperactivity in the SGC before and after rTMS treatment was measured. Subgenual cingulate cortex hyperactivity activity was quantified using significant current density (SCD), and effective connectivity between the left DLPFC and SGC was computed using significant current scattering (SCS). Both measures were computed around TMS evoked potentials standard peak latencies prior to rTMS and after rTMS treatment, comparing patients with MMD treated with active and sham rTMS. Patients with MDD were assessed with the 17-item Hamilton Rating Scale for Depression. Results: Of 121 patients with MDD in the initial trial, 30 (15 [50.0%] women) were compared with 30 healthy controls (15 [50.0%] women) at rTMS treatment baseline. The mean (SD) age of the cohort with MDD was 39.1 (10.9) years, and the mean (SD) age of healthy controls was 37.0 (11.0) years. Following rTMS treatment, 26 patients with MDD who had active rTMS treatment (21.5%) were compared with 17 patients with MDD who had sham treatment (14.0%). At baseline, the SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after TMS pulse were higher in participants with MDD compared with healthy controls (SCD: 1.04 × 10-6 [1.41 × 10-6] μA/mm2 vs 3.8 × 10-7 [7.8 × 10-7] μA/mm2; z = -2.95; P = .004; SCS: 0.87 [0.86] mm vs 0.54 [0.87] mm; z = -2.27; P = .02). Baseline source current density was able to classify MDD with 77% accuracy. Scores on the 17-item Hamilton Rating Scale for Depression were correlated with current density at the SGC (ρ = 0.41; P = .03). After rTMS treatment, SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after rTMS pulse were attenuated to approximately the standard TMS-evoked potential latencies in the active rTMS group compared with the sham rTMS group (SCD: 1.57 × 10-7 [3.67 × 10-7] μA/mm2 vs 7.00 × 10-7 [7.51 × 10-7] μA/mm2; z = -2.91; P = .004; SCS: 0.20 [0.44] mm vs 0.74 [0.73] mm; z = -2.78; P = .006). Additionally, the SGC SCS change was correlated with symptom improvement on the 17-item Hamilton Rating Scale for Depression in the active rTMS group (ρ = 0.58; P = .047). Conclusions and Relevance: The findings of this study further implicate left DLPFC-SGC effective connectivity and SGC excitability in the pathophysiology of MDD and treatment with rTMS. These findings suggest that DLPFC-SGC connectivity may be a marker of rTMS treatment responsiveness. Trial Registration: ClinicalTrials.gov identifier: NCT01515215.

AB - Importance: Hyperactivity in the subgenual cingulate cortex (SGC) is associated with major depressive disorder (MDD) and anticorrelated with activity in the dorsolateral prefrontal cortex (DLPFC). This association was found to be predictive of responsiveness to repetitive transcranial magnetic stimulation (rTMS) treatment. Such findings suggest that DLPFC-SGC connectivity is important for understanding both the therapeutic mechanism of rTMS in patients with MDD and the underlying pathophysiology of MDD. Objective: To evaluate SGC hyperactivity in patients with MDD before and after rTMS treatment. Design, Setting, and Participants: In this diagnostic study, among participants recruited from the adult and geriatric mood and anxiety services at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, who had participated in a randomized clinical trial, baseline SGC activity of patients with MDD was compared with healthy controls. In patients with MDD, SGC activity was compared before and after active or sham high-frequency rTMS treatment. Data collection started in July 2008 and concluded in March 2012. Neurophysiological data analysis started in January 2017 and ended in May 2018. Main Outcomes and Measures: Hyperactivity in the SGC before and after rTMS treatment was measured. Subgenual cingulate cortex hyperactivity activity was quantified using significant current density (SCD), and effective connectivity between the left DLPFC and SGC was computed using significant current scattering (SCS). Both measures were computed around TMS evoked potentials standard peak latencies prior to rTMS and after rTMS treatment, comparing patients with MMD treated with active and sham rTMS. Patients with MDD were assessed with the 17-item Hamilton Rating Scale for Depression. Results: Of 121 patients with MDD in the initial trial, 30 (15 [50.0%] women) were compared with 30 healthy controls (15 [50.0%] women) at rTMS treatment baseline. The mean (SD) age of the cohort with MDD was 39.1 (10.9) years, and the mean (SD) age of healthy controls was 37.0 (11.0) years. Following rTMS treatment, 26 patients with MDD who had active rTMS treatment (21.5%) were compared with 17 patients with MDD who had sham treatment (14.0%). At baseline, the SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after TMS pulse were higher in participants with MDD compared with healthy controls (SCD: 1.04 × 10-6 [1.41 × 10-6] μA/mm2 vs 3.8 × 10-7 [7.8 × 10-7] μA/mm2; z = -2.95; P = .004; SCS: 0.87 [0.86] mm vs 0.54 [0.87] mm; z = -2.27; P = .02). Baseline source current density was able to classify MDD with 77% accuracy. Scores on the 17-item Hamilton Rating Scale for Depression were correlated with current density at the SGC (ρ = 0.41; P = .03). After rTMS treatment, SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after rTMS pulse were attenuated to approximately the standard TMS-evoked potential latencies in the active rTMS group compared with the sham rTMS group (SCD: 1.57 × 10-7 [3.67 × 10-7] μA/mm2 vs 7.00 × 10-7 [7.51 × 10-7] μA/mm2; z = -2.91; P = .004; SCS: 0.20 [0.44] mm vs 0.74 [0.73] mm; z = -2.78; P = .006). Additionally, the SGC SCS change was correlated with symptom improvement on the 17-item Hamilton Rating Scale for Depression in the active rTMS group (ρ = 0.58; P = .047). Conclusions and Relevance: The findings of this study further implicate left DLPFC-SGC effective connectivity and SGC excitability in the pathophysiology of MDD and treatment with rTMS. These findings suggest that DLPFC-SGC connectivity may be a marker of rTMS treatment responsiveness. Trial Registration: ClinicalTrials.gov identifier: NCT01515215.

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