Advertisement

Efficacy of Transcranial Magnetic Stimulation Targets for Depression Is Related to Intrinsic Functional Connectivity with the Subgenual Cingulate

  • Michael D. Fox
    Correspondence
    Address correspondence to Michael D. Fox, M.D., Ph.D., Massachusetts General Hospital, Department of Neurology, WACC 8-835, 55 Fruit St., Boston, MA 02114
    Affiliations
    Partners Neurology, Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

    Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

    Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Randy L. Buckner
    Affiliations
    Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, Boston, Massachusetts

    Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts

    Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts
    Search for articles by this author
  • Matthew P. White
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California
    Search for articles by this author
  • Michael D. Greicius
    Affiliations
    Functional Imaging in Neuropsychiatric Disorders Lab, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California
    Search for articles by this author
  • Alvaro Pascual-Leone
    Affiliations
    Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

    Institut Guttmann, Hospital de Neurorehabilitació, Institut Universitari adscrit a la Universitat Autònoma de Barcelona, Barcelona, Spain
    Search for articles by this author

      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.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Wagner T.
        • Valero-Cabre A.
        • Pascual-Leone A.
        Noninvasive human brain stimulation.
        Annu Rev Biomed Eng. 2007; 9: 527-565
        • Kobayashi M.
        • Pascual-Leone A.
        Transcranial magnetic stimulation in neurology.
        Lancet Neurol. 2003; 2: 145-156
        • Hallett M.
        Transcranial magnetic stimulation: A primer.
        Neuron. 2007; 55: 187-199
        • Valero-Cabre A.
        • Payne B.R.
        • Rushmore J.
        • Lomber S.G.
        • Pascual-Leone A.
        Impact of repetitive transcranial magnetic stimulation of the parietal cortex on metabolic brain activity: A 14C-2DG tracing study in the cat.
        Exp Brain Res. 2005; 163: 1-12
        • Valero-Cabre A.
        • Payne B.R.
        • Pascual-Leone A.
        Opposite impact on 14C-2-deoxyglucose brain metabolism following patterns of high and low frequency repetitive transcranial magnetic stimulation in the posterior parietal cortex.
        Exp Brain Res. 2007; 176: 603-615
        • Siebner H.R.
        • Bergmann T.O.
        • Bestmann S.
        • Massimini M.
        • Johansen-Berg H.
        • Mochizuki H.
        • et al.
        Consensus paper: Combining transcranial stimulation with neuroimaging.
        Brain Stimul. 2009; 2: 58-80
        • Ruff C.C.
        • Driver J.
        • Bestmann S.
        Combining TMS and fMRI: From 'virtual lesions' to functional-network accounts of cognition.
        Cortex. 2009; 45: 1043-1049
        • Ferreri F.
        • Pasqualetti P.
        • Maatta S.
        • Ponzo D.
        • Ferrarelli F.
        • Tononi G.
        • et al.
        Human brain connectivity during single and paired pulse transcranial magnetic stimulation.
        Neuroimage. 2011; 54: 90-201
        • Lisanby S.H.
        • Belmaker R.H.
        Animal models of the mechanisms of action of repetitive transcranial magnetic stimulation (RTMS): Comparisons with electroconvulsive shock (ECS).
        Depress Anxiety. 2000; 12: 178-187
        • Fox M.D.
        • Halko M.A.
        • Eldaief M.C.
        • Pascual-Leone A.
        Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS) [published online ahead of print March 19].
        Neuroimage. 2012;
        • O'Reardon J.P.
        • Solvason H.B.
        • Janicak P.G.
        • Sampson S.
        • Isenberg K.E.
        • Nahas Z.
        • et al.
        Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: A multisite randomized controlled trial.
        Biol Psychiatry. 2007; 62: 1208-1216
        • Padberg F.
        • George M.S.
        Repetitive transcranial magnetic stimulation of the prefrontal cortex in depression.
        Exp Neurol. 2009; 219: 2-13
        • George M.S.
        • Wassermann E.M.
        • Williams W.A.
        • Callahan A.
        • Ketter T.A.
        • Basser P.
        • et al.
        Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression.
        Neuroreport. 1995; 6: 1853-1856
        • Pascual-Leone A.
        • Rubio B.
        • Pallardo F.
        • Catala M.D.
        Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression.
        Lancet. 1996; 348: 233-237
        • Mayberg H.S.
        Defining the neural circuitry of depression: Toward a new nosology with therapeutic implications.
        Biol Psychiatry. 2007; 61: 729-730
        • Drevets W.C.
        • Savitz J.
        • Trimble M.
        The subgenual anterior cingulate cortex in mood disorders.
        CNS Spectr. 2008; 13: 663-681
        • Mayberg H.S.
        • Lozano A.M.
        • Voon V.
        • McNeely H.E.
        • Seminowicz D.
        • Hamani C.
        • et al.
        Deep brain stimulation for treatment-resistant depression.
        Neuron. 2005; 45: 651-660
        • Mayberg H.S.
        Targeted electrode-based modulation of neural circuits for depression.
        J Clin Invest. 2009; 119: 717-725
        • George M.S.
        • Wassermann E.M.
        • Kimbrell T.A.
        • Little J.T.
        • Williams W.E.
        • Danielson A.L.
        • et al.
        Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: A placebo-controlled crossover trial.
        Am J Psychiatry. 1997; 154: 1752-1756
        • George M.S.
        • Stallings L.E.
        • Speer A.M.
        • Nahas Z.
        • Spicer K.M.
        • Vincent D.J.
        • et al.
        Prefrontal repetitive transcranial magnetic stimulation (rTMS) changes relative perfusion locally and remotely.
        Hum Psychopharmacol. 1999; 14: 161-170
        • Kimbrell T.A.
        • Dunn R.T.
        • George M.S.
        • Danielson A.L.
        • Willis M.W.
        • Repella J.D.
        • et al.
        Left prefrontal-repetitive transcranial magnetic stimulation (rTMS) and regional cerebral glucose metabolism in normal volunteers.
        Psychiatry Res. 2002; 115: 101-113
        • Narushima K.
        • McCormick L.M.
        • Yamada T.
        • Thatcher R.W.
        • Robinson R.G.
        Subgenual cingulate theta activity predicts treatment response of repetitive transcranial magnetic stimulation in participants with vascular depression.
        J Neuropsychiatry Clin Neurosci. 2010; 22: 75-84
        • Kito S.
        • Fujita K.
        • Koga Y.
        Regional cerebral blood flow changes after low-frequency transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in treatment-resistant depression.
        Neuropsychobiology. 2008; 58: 29-36
        • Kito S.
        • Hasegawa T.
        • Koga Y.
        Neuroanatomical correlates of therapeutic efficacy of low-frequency right prefrontal transcranial magnetic stimulation in treatment-resistant depression.
        Psychiatry Clin Neurosci. 2011; 65: 175-182
        • Paus T.
        • Castro-Alamancos M.A.
        • Petrides M.
        Cortico-cortical connectivity of the human mid-dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation.
        Eur J Neurosci. 2001; 14: 1405-1411
        • Li X.
        • Nahas Z.
        • Kozel F.A.
        • Anderson B.
        • Bohning D.E.
        • George M.S.
        Acute left prefrontal transcranial magnetic stimulation in depressed patients is associated with immediately increased activity in prefrontal cortical as well as subcortical regions.
        Biol Psychiatry. 2004; 55: 882-890
        • Teneback C.C.
        • Nahas Z.
        • Speer A.M.
        • Molloy M.
        • Stallings L.E.
        • Spicer K.M.
        • et al.
        Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS.
        J Neuropsychiatry Clin Neurosci. 1999; 11: 426
        • Nahas Z.
        • Lomarev M.
        • Roberts D.R.
        • Shastri A.
        • Lorberbaum J.P.
        • Teneback C.
        • et al.
        Unilateral left prefrontal transcranial magnetic stimulation (TMS) produces intensity-dependent bilateral effects as measured by interleaved BOLD fMRI.
        Biol Psychiatry. 2001; 50: 712-720
        • Speer A.M.
        • Kimbrell T.A.
        • Wassermann E.M.
        • D Repella J.
        • Willis M.W.
        • Herscovitch P.
        • Post R.M.
        Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients.
        Biol Psychiatry. 2000; 48: 1133-1141
        • Mottaghy F.M.
        • Keller C.E.
        • Gangitano M.
        • Ly J.
        • Thall M.
        • Parker J.A.
        • Pascual-Leone A.
        Correlation of cerebral blood flow and treatment effects of repetitive transcranial magnetic stimulation in depressed patients.
        Psychiatry Res. 2002; 115: 1-14
        • Eisenegger C.
        • Treyer V.
        • Fehr E.
        • Knoch D.
        Time-course of “off-line” prefrontal rTMS effects–a PET study.
        Neuroimage. 2008; 42: 379-384
        • Knoch D.
        • Treyer V.
        • Regard M.
        • Muri R.M.
        • Buck A.
        • Weber B.
        Lateralized and frequency-dependent effects of prefrontal rTMS on regional cerebral blood flow.
        Neuroimage. 2006; 31: 641-648
        • Speer A.M.
        • Willis M.W.
        • Herscovitch P.
        • Daube-Witherspoon M.
        • Shelton J.R.
        • Benson B.E.
        • et al.
        Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: II.
        Biol Psychiatry. 2003; 54: 826-832
        • Ferrarelli F.
        • Haraldsson H.M.
        • Barnhart T.E.
        • Roberts A.D.
        • Oakes T.R.
        • Massimini M.
        • et al.
        A [17F]-fluoromethane PET/TMS study of effective connectivity.
        Brain Res Bull. 2004; 64: 103-113
        • Fitzgerald P.B.
        • Hoy K.
        • McQueen S.
        • Maller J.J.
        • Herring S.
        • Segrave R.
        • et al.
        A randomized trial of rTMS targeted with MRI based neuro-navigation in treatment-resistant depression.
        Neuropsychopharmacology. 2009; 34: 1255-1262
        • Herbsman T.
        • Avery D.
        • Ramsey D.
        • Holtzheimer P.
        • Wadjik C.
        • Hardaway F.
        • et al.
        More lateral and anterior prefrontal coil location is associated with better repetitive transcranial magnetic stimulation antidepressant response.
        Biol Psychiatry. 2009; 66: 509-515
        • Herwig U.
        • Padberg F.
        • Unger J.
        • Spitzer M.
        • Schonfeldt-Lecuona C.
        Transcranial magnetic stimulation in therapy studies: Examination of the reliability of “standard” coil positioning by neuronavigation.
        Biol Psychiatry. 2001; 50: 58-61
        • Ahdab R.
        • Ayache S.S.
        • Brugières P.
        • Goujon C.
        • Lefaucheur J.-P.
        Comparison of “standard” and “navigated” procedures of TMS coil positioning over motor, premotor and prefrontal targets in patients with chronic pain and depression.
        Neurophysiol Clin. 2010; 40: 27-36
        • George M.S.
        • Wassermann E.M.
        • Williams W.A.
        • Steppel J.
        • Pascual-Leone A.
        • Basser P.
        • et al.
        Changes in mood and hormone levels after rapid-rate transcranial magnetic stimulation (rTMS) of the prefrontal cortex.
        J Neuropsychiatry Clin Neurosci. 1996; 8: 172-180
        • Herwig U.
        • Satrapi P.
        • Schonfeldt-Lecuona C.
        Using the international 10-20 EEG system for positioning of transcranial magnetic stimulation.
        Brain Topogr. 2003; 16: 95-99
        • Rusjan P.M.
        • Barr M.S.
        • Farzan F.
        • Arenovich T.
        • Maller J.J.
        • Fitzgerald P.B.
        • Daskalakis Z.J.
        Optimal transcranial magnetic stimulation coil placement for targeting the dorsolateral prefrontal cortex using novel magnetic resonance image-guided neuronavigation.
        Hum Brain Mapp. 2010; 31: 1643-1652
        • Paillère Martinot M.-L.
        • Galinowski A.
        • Ringuenet D.
        • Gallarda T.
        • Lefaucheur J.-P.
        • Bellivier F.
        • et al.
        Influence of prefrontal target region on the efficacy of repetitive transcranial magnetic stimulation in patients with medication-resistant depression: A [(18)F]-fluorodeoxyglucose PET and MRI study.
        Int J Neuropsychopharmacol. 2010; 13: 45-59
        • Herwig U.
        • Lampe Y.
        • Juengling F.D.
        • Wunderlich A.
        • Walter H.
        • Spitzer M.
        • Schönfeldt-Lecuona C.
        Add-on rTMS for treatment of depression: A pilot study using stereotaxic coil-navigation according to PET data.
        J Psychiatr Res. 2003; 37: 267-275
        • Garcia-Toro M.
        • Salva J.
        • Daumal J.
        • Andres J.
        • Romera M.
        • Lafau O.
        • et al.
        High (20-Hz) and low (1-Hz) frequency transcranial magnetic stimulation as adjuvant treatment in medication-resistant depression.
        Psychiatry Res. 2006; 146: 53-57
        • Biswal B.
        • Yetkin F.
        • Haughton V.
        • Hyde J.
        Functional connectivity in the motor cortex of resting human brain using echo-planar MRI.
        Magn Reson Med. 1995; 34: 537-541
        • Fox M.D.
        • Raichle M.E.
        Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging.
        Nat Rev Neurosci. 2007; 8: 700-711
        • Van Dijk K.R.
        • Hedden T.
        • Venkataraman A.
        • Evans K.C.
        • Lazar S.W.
        • Buckner R.L.
        Intrinsic functional connectivity as a tool for human connectomics: Theory, properties, and optimization.
        J Neurophysiol. 2010; 103: 297-321
        • Fox M.D.
        • Snyder A.Z.
        • Vincent J.L.
        • Corbetta M.
        • Van Essen D.C.
        • Raichle M.E.
        The human brain is intrinsically organized into dynamic, anticorrelated functional networks.
        Proc Natl Acad Sci U S A. 2005; 102: 9673-9678
        • Wu J.
        • Buchsbaum M.S.
        • Gillin J.C.
        • Tang C.
        • Cadwell S.
        • Wiegand M.
        • et al.
        Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex.
        Am J Psychiatry. 1999; 156: 1149-1158
        • Mayberg H.S.
        • Brannan S.K.
        • Tekell J.L.
        • Silva J.A.
        • Mahurin R.K.
        • McGinnis S.
        • Jerabek P.A.
        Regional metabolic effects of fluoxetine in major depression: Serial changes and relationship to clinical response.
        Biol Psychiatry. 2000; 48: 830-843
        • Drevets W.C.
        • Bogers W.
        • Raichle M.E.
        Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism.
        Eur Neuropsychopharmacol. 2002; 12: 527-544
        • Nahas Z.
        • Teneback C.
        • Chae J.H.
        • Mu Q.
        • Molnar C.
        • Kozel F.A.
        • et al.
        Serial vagus nerve stimulation functional MRI in treatment-resistant depression.
        Neuropsychopharmacology. 2007; 32: 1649-1660
        • Cho S.S.
        • Strafella A.P.
        rTMS of the left dorsolateral prefrontal cortex modulates dopamine release in the ipsilateral anterior cingulate cortex and orbitofrontal cortex.
        PloS One. 2009; 4: e6725
        • Rajkowska G.
        • Goldman-Rakic P.S.
        Cytoarchitectonic definition of prefrontal areas in the normal human cortex: II.
        Cereb Cortex. 1995; 5: 323-337
        • Schutter D.J.
        • Laman D.M.
        • van Honk J.
        • Vergouwen A.C.
        • Koerselman G.F.
        Partial clinical response to 2 weeks of 2 Hz repetitive transcranial magnetic stimulation to the right parietal cortex in depression.
        Int J Neuropsychopharmacol. 2009; 12: 643-650
        • Schutter D.J.
        • van Honk J.
        A framework for targeting alternative brain regions with repetitive transcranial magnetic stimulation in the treatment of depression.
        J Psychiatry Neurosci. 2005; 30: 91-97
        • Greicius M.D.
        • Flores B.H.
        • Menon V.
        • Glover G.H.
        • Solvason H.B.
        • Kenna H.
        • et al.
        Resting-state functional connectivity in major depression: Abnormally increased contributions from subgenual cingulate cortex and thalamus.
        Biol Psychiatry. 2007; 62: 429-437
        • Koenigs M.
        • Grafman J.
        The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex.
        Behav Brain Res. 2009; 201: 239-243
        • Fitzgerald P.B.
        • Oxley T.J.
        • Laird A.R.
        • Kulkarni J.
        • Egan G.F.
        • Daskalakis Z.J.
        An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression.
        Psychiatry Res. 2006; 148: 33-45
        • Steele J.D.
        • Currie J.
        • Lawrie S.M.
        • Reid I.
        Prefrontal cortical functional abnormality in major depressive disorder: A stereotactic meta-analysis.
        J Affect Disord. 2007; 101: 1-11
        • Fitzgerald P.B.
        • Laird A.R.
        • Maller J.
        • Daskalakis Z.J.
        A meta-analytic study of changes in brain activation in depression.
        Hum Brain Mapp. 2008; 29: 683-695
        • Koenigs M.
        • Huey E.D.
        • Calamia M.
        • Raymont V.
        • Tranel D.
        • Grafman J.
        Distinct regions of prefrontal cortex mediate resistance and vulnerability to depression.
        J Neurosci. 2008; 28: 12341-12348
        • Paus T.
        • Barrett J.
        Transcranial magnetic stimulation (TMS) of the human frontal cortex: Implications for repetitive TMS treatment of depression.
        J Psychiatry Neurosci. 2004; 29: 268-279
        • Murphy K.
        • Birn R.M.
        • Handwerker D.A.
        • Jones T.B.
        • Bandettini P.A.
        The impact of global signal regression on resting state correlations: Are anti-correlated networks introduced?.
        Neuroimage. 2009; 44: 893-905
        • Fox M.D.
        • Zhang D.
        • Snyder A.Z.
        • Raichle M.E.
        The global signal and observed anticorrelated resting state brain networks.
        J Neurophysiol. 2009; 101: 3270-3283
        • Anderson J.S.
        • Druzgal T.J.
        • Lopez-Larson M.
        • Jeong E.-K.
        • Desai K.
        • Yurgelun-Todd D.
        Network anticorrelations, global regression, and phase-shifted soft tissue correction.
        Hum Brain Mapp. 2011; 32: 919-934
        • Chai X.J.
        • Castanon A.N.
        • Ongur D.
        • Whitfield-Gabrieli S.
        Anticorrelations in resting state networks without global signal regression.
        Neuroimage. 2012; 59: 1420-1428
        • Petrides M.
        • Pandya D.N.
        Dorsolateral prefrontal cortex: Comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns.
        Eur J Neurosci. 1999; 11: 1011-1036
        • Vogt B.A.
        • Pandya D.N.
        Cingulate cortex of the rhesus monkey: II.
        J Comp Neurol. 1987; 262: 271-289
        • Sridharan D.
        • Levitin D.J.
        • Menon V.
        A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks.
        Proc Natl Acad Sci U S A. 2008; 105: 12569-12574
        • Groenewegen H.J.
        • Galis-de Graaf Y.
        • Smeets W.J.
        Integration and segregation of limbic cortico-striatal loops at the thalamic level: An experimental tracing study in rats.
        J Chem Neuroanat. 1999; 16: 167-185
        • Van Essen D.C.
        • Dierker D.L.
        Surface-based and probabilistic atlases of primate cerebral cortex.
        Neuron. 2007; 56: 209-225
        • Hamani C.
        • Nobrega J.N.
        • Lozano A.M.
        Deep brain stimulation in clinical practice and in animal models.
        Clin Pharmacol Ther. 2010; 88: 559-562