Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate
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Background Transcranial magnetic stimulation (TMS) to the left dorsolateral prefrontal cortex (DLPFC) is used clinically for the treatment of depression. However, the antidepressant mechanism remains unknown and its therapeutic efficacy remains limited. Recent data suggest that some left DLPFC targets are more effective than others; however, the reasons for this heterogeneity and how to capitalize on this information remain unclear.Methods Intrinsic (resting state) functional magnetic resonance imaging data from 98 normal subjects were used to compute functional connectivity with various left DLPFC TMS targets employed in the literature. Differences in functional connectivity related to differences in previously reported clinical efficacy were identified. This information was translated into a connectivity-based targeting strategy to identify optimized left DLPFC TMS coordinates. Results in normal subjects were tested for reproducibility in an independent cohort of 13 patients with depression.Results Differences in functional connectivity were related to previously reported differences in clinical efficacy across a distributed set of cortical and limbic regions. Dorsolateral prefrontal cortex TMS sites with better clinical efficacy were more negatively correlated (anticorrelated) with the subgenual cingulate. Optimum connectivity-based stimulation coordinates were identified in Brodmann area 46. Results were reproducible in patients with depression.Conclusions Reported antidepressant efficacy of different left DLPFC TMS sites is related to the anticorrelation of each site with the subgenual cingulate, potentially lending insight into the antidepressant mechanism of TMS and suggesting a role for intrinsically anticorrelated networks in depression. These results can be translated into a connectivity-based targeting strategy for focal brain stimulation that might be used to optimize clinical response.
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Recent studies indicate that rTMS affects both local excitability in the stimulated brain region and broader functional connectivity across networks; at least some clinical effects may be due more to changes in functional connectivity than local effects.
“Recent studies indicate that rTMS affects both local excitability in the stimulated brain region and broader functional connectivity across networks. At least some of the clinical effects may be due more to changes in functional connectivity across the brain regions than local effects on the stimulated region itself (35).”
From Adaptive trial for the treatment of depressive symptoms associated with concussion using accelerated intermittent theta burst stimulation (ADEPT): rationale, design and methods (2025) · cites this paper as [35]
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Experimental — accuracy not yet measuredThe dlPFC region showing greatest efficacy in MDD is anticorrelated to the sgCC and corresponds well to the SN's dlPFC node.
“For example, the dlPFC region showing greatest efficacy in MDD has been reported to be a region anticorrelated to the sgCC, which also corresponds well to the SN’s dlPFC node (Fox et al., 2012).”
From Cortico-striatal-thalamic loop circuits of the salience network: A central pathway in psychiatric disease and treatment (2016) · cites this paper as Fox et al., 2012
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“For example, the dlPFC region showing greatest efficacy in MDD has been reported to be a region anticorrelated to the sgCC, which also corresponds well to the SN’s dlPFC node (Fox et al., 2012).”
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- Authors
- Fox, M. D., Buckner, R. L., White, M. P., Greicius, M. D., & Pascual-Leone, A.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Stanford Medicine (US)
- Corresponding author
- Fox, Michael D.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 72
- Issue
- 7
- Pages
- 595-603
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4120275
- OpenAlex
- W1988751658
- Cited by
- 1,270
- References
- 77
- Citations by year
- 2026: 181 · 2025: 141 · 2024: 134 · 2023: 110 · 2022: 110 · 2021: 133 · 2020: 94 · 2019: 77 · 2018: 70 · 2017: 68 · 2016: 42 · 2015: 48 · 2014: 36 · 2013: 19 · 2012: 6
- FWCI
- 17.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R25NS065743)
- National Institutes of Health and National Center for Research Resources: Harvard Clinical and Translational Science Center (UL1 RR025758)
- Howard Hughes Medical Institute
- Dana Foundation
- Topics
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- transcranial magnetic stimulation, depression, dorsolateral prefrontal cortex, subgenual cingulate, resting-state functional connectivity, Brodmann area 46, antidepressant mechanism
- MeSH terms
- Adult, Brain Mapping, Major Depressive Disorder, Female, Humans, Image Processing, Computer-Assisted, Functional Laterality, Magnetic Resonance Imaging, Male, Nerve Net, Oxygen, Psychiatric Status Rating Scales, Linear Models, Prefrontal Cortex, Transcranial Magnetic Stimulation, Young Adult
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