Cerebral Cortex doi:10.1093/cercor/bhm167 Anatomical Connectivity of the Subgenual Cingulate Region Targeted with Deep Brain Stimulation for Treatment-Resistant Depression

Chronic deep brain stimulation (DBS) of subgenual cingulate white matter results in dramatic remission of symptoms in some previously treatment-resistant depression patients. The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections. We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects. We defined 2 distinct regions within anterior cingulate cortex based on anatomical connectivity: a pregenual region strongly connected to medial prefrontal and anterior midcingulate cortex and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. The location of electrode contact points from 9 patients successfully treated with DBS lies within this subgenual region. The anatomical connectivity of the subgenual cingulate region targeted with DBS for depression supports the hypothesis that treatment efficacy is mediated via effects on a distributed network of frontal, limbic, and visceromotor brain regions. At present, targeting of DBS for depression is based on landmarks visible in conventional magnetic resonance imaging. Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting. We hypothesize that the subgenual region with greatest connectivity across the distributed network described here may prove most effective.

[1]  P. Goldman-Rakic,et al.  Direct and indirect pathways from the amygdala to the frontal lobe in rhesus monkeys , 1981, The Journal of comparative neurology.

[2]  D. Pandya,et al.  Cingulate cortex of the rhesus monkey: II. Cortical afferents , 1987, The Journal of comparative neurology.

[3]  C. Geula,et al.  Cytoarchitecture and neural afferents of orbitofrontal cortex in the brain of the monkey , 1992, The Journal of comparative neurology.

[4]  M. Gabriel,et al.  Neurobiology of Cingulate Cortex and Limbic Thalamus , 1993 .

[5]  Terry M. Peters,et al.  3D statistical neuroanatomical models from 305 MRI volumes , 1993, 1993 IEEE Conference Record Nuclear Science Symposium and Medical Imaging Conference.

[6]  B. Vogt,et al.  Connections of the Monkey Cingulate Cortex , 1993 .

[7]  Alex Pothen,et al.  A spectral algorithm for envelope reduction of sparse matrices , 1993, Supercomputing '93. Proceedings.

[8]  S. Haber,et al.  Primate cingulostriatal projection: Limbic striatal versus sensorimotor striatal input , 1994, The Journal of comparative neurology.

[9]  C. Beaulieu,et al.  Determinants of anisotropic water diffusion in nerves , 1994, Magnetic resonance in medicine.

[10]  J. Price,et al.  Architectonic subdivision of the orbital and medial prefrontal cortex in the macaque monkey , 1994, The Journal of comparative neurology.

[11]  B. Vogt,et al.  Human cingulate cortex: Surface features, flat maps, and cytoarchitecture , 1995, The Journal of comparative neurology.

[12]  B. Horwitz,et al.  Brain activity during transient sadness and happiness in healthy women. , 1995, The American journal of psychiatry.

[13]  A spectral algorithm for envelope reduction of sparse matrices , 1995, Numer. Linear Algebra Appl..

[14]  J. Price,et al.  Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys , 1995, The Journal of comparative neurology.

[15]  J. Price,et al.  Sensory and premotor connections of the orbital and medial prefrontal cortex of macaque monkeys , 1995, The Journal of comparative neurology.

[16]  E. Lynd-Balta,et al.  The orbital and medial prefrontal circuit through the primate basal ganglia , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  Alan C. Evans,et al.  In vivo morphometry of the intrasulcal gray matter in the human cingulate, paracingulate, and superior‐rostral sulci: Hemispheric asymmetries, gender differences and probability maps , 1996, The Journal of comparative neurology.

[18]  S. Carmichael,et al.  Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys. , 1996, The Journal of comparative neurology.

[19]  Alan C. Evans,et al.  Human cingulate and paracingulate sulci: pattern, variability, asymmetry, and probabilistic map. , 1996, Cerebral cortex.

[20]  H. Mayberg.  Limbic-cortical dysregulation: a proposed model of depression. , 1997, The Journal of neuropsychiatry and clinical neurosciences.

[21]  J. Price,et al.  Prefrontal cortical projections to the hypothalamus in Macaque monkeys , 1998, The Journal of comparative neurology.

[22]  H. Barbas,et al.  Topographic Organization of Connections between the Hypothalamus and Prefrontal Cortex in the Rhesus Monkey , 2022 .

[23]  J. Price,et al.  Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in Macaque monkeys , 1998, The Journal of comparative neurology.

[24]  D. Pandya,et al.  Fiber system linking the mid‐dorsolateral frontal cortex with the retrosplenial/presubicular region in the rhesus monkey , 1999, The Journal of comparative neurology.

[25]  L. Parsons,et al.  Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. , 1999, The American journal of psychiatry.

[26]  P. Jerabek,et al.  Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response , 2000, Biological Psychiatry.

[27]  Mark Jenkinson,et al.  Global optimisation for robust affine registration , 2000, NeuroImage.

[28]  T. Insel,et al.  Subcortical projections of area 25 (subgenual cortex) of the macaque monkey , 2000, The Journal of comparative neurology.

[29]  C. Cavada,et al.  The anatomical connections of the macaque monkey orbitofrontal cortex. A review. , 2000, Cerebral cortex.

[30]  J. Price,et al.  Prefrontal cortical projections to the striatum in macaque monkeys: Evidence for an organization related to prefrontal networks , 2000, The Journal of comparative neurology.

[31]  H. Sackeim,et al.  Decreased regional brain metabolism after ect. , 2001, The American journal of psychiatry.

[32]  G. Pearlson,et al.  Diffusion Tensor Imaging and Axonal Tracking in the Human Brainstem , 2001, NeuroImage.

[33]  Stephen M. Smith,et al.  A global optimisation method for robust affine registration of brain images , 2001, Medical Image Anal..

[34]  K. Nakano,et al.  Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata , 2001, Brain Research.

[35]  P. Maruff,et al.  Hemispheric and gender-related differences in the gross morphology of the anterior cingulate/paracingulate cortex in normal volunteers: an MRI morphometric study. , 2001, Cerebral cortex.

[36]  M. Cuesta,et al.  [Neurobiology of depression]. , 2002, Anales del sistema sanitario de Navarra.

[37]  Marcus E Raichle,et al.  Volumetric reduction in left subgenual prefrontal cortex in early onset depression , 2002, Biological Psychiatry.

[38]  M. Raichle,et al.  Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism , 2002, European Neuropsychopharmacology.

[39]  Á. Pascual-Leone,et al.  Correlation of cerebral blood flow and treatment effects of repetitive transcranial magnetic stimulation in depressed patients , 2002, Psychiatry Research: Neuroimaging.

[40]  Helen S Mayberg,et al.  Unmasking disease-specific cerebral blood flow abnormalities: mood challenge in patients with remitted unipolar depression. , 2002, The American journal of psychiatry.

[41]  Stephen M Smith,et al.  Fast robust automated brain extraction , 2002, Human brain mapping.

[42]  A. Perrin.  High-Speed Imaging Reveals Neurophysiological Links to Behavior in an Animal Model of Depression , 2002 .

[43]  H. Mayberg.  Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. , 2003, British medical bulletin.

[44]  J. Price,et al.  Architectonic subdivision of the human orbital and medial prefrontal cortex , 2003, The Journal of comparative neurology.

[45]  Timothy Edward John Behrens,et al.  Characterization and propagation of uncertainty in diffusion‐weighted MR imaging , 2003, Magnetic resonance in medicine.

[46]  H. Barbas,et al.  Serial pathways from primate prefrontal cortex to autonomic areas may influence emotional expression , 2003, BMC Neuroscience.

[47]  Timothy Edward John Behrens,et al.  Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging , 2003, Nature Neuroscience.

[48]  S. Holland,et al.  A Preliminary fMRI Study of Sustained Attention in Euthymic, Unmedicated Bipolar Disorder , 2004, Neuropsychopharmacology.

[49]  Mark W. Woolrich,et al.  Advances in functional and structural MR image analysis and implementation as FSL , 2004, NeuroImage.

[50]  Dennis Velakoulis,et al.  Individual differences in anterior cingulate/paracingulate morphology are related to executive functions in healthy males. , 2004, Cerebral cortex.

[51]  Timothy Edward John Behrens,et al.  Changes in connectivity profiles define functionally distinct regions in human medial frontal cortex. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Warren D Taylor,et al.  Late-life depression and microstructural abnormalities in dorsolateral prefrontal cortex white matter. , 2004, The American journal of psychiatry.

[53]  Anthony R. McIntosh,et al.  Limbic–frontal circuitry in major depression: a path modeling metanalysis , 2004, NeuroImage.

[54]  Mark Lau,et al.  Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. , 2004, Archives of general psychiatry.

[55]  Timothy Edward John Behrens,et al.  Quantitative Investigation of Connections of the Prefrontal Cortex in the Human and Macaque using Probabilistic Diffusion Tractography , 2005, The Journal of Neuroscience.

[56]  Timothy Edward John Behrens,et al.  Functional-anatomical validation and individual variation of diffusion tractography-based segmentation of the human thalamus. , 2005, Cerebral cortex.

[57]  Timothy Edward John Behrens,et al.  Relating connectional architecture to grey matter function using diffusion imaging , 2005, Philosophical Transactions of the Royal Society B: Biological Sciences.

[58]  A. Meyer-Lindenberg,et al.  5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression , 2005, Nature Neuroscience.

[59]  Timothy Edward John Behrens,et al.  Connectivity of the human periventricular-periaqueductal gray region. , 2005, Journal of neurosurgery.

[60]  B. Vogt,et al.  Architecture and neurocytology of monkey cingulate gyrus , 2005, The Journal of comparative neurology.

[61]  Nancy C Andreasen,et al.  Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: diagnostic specificity and prognostic implications. , 2005, The American journal of psychiatry.

[62]  A. Lozano,et al.  Deep Brain Stimulation for Treatment-Resistant Depression , 2005, Neuron.

[63]  K Nobuhara,et al.  Frontal white matter anisotropy and symptom severity of late-life depression: a magnetic resonance diffusion tensor imaging study , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[64]  S. Haber,et al.  Reward-Related Cortical Inputs Define a Large Striatal Region in Primates That Interface with Associative Cortical Connections, Providing a Substrate for Incentive-Based Learning , 2006, The Journal of Neuroscience.

[65]  Dennis Velakoulis,et al.  The influence of sulcal variability on morphometry of the human anterior cingulate and paracingulate cortex , 2006, NeuroImage.

[66]  D. Pandya,et al.  Fiber Pathways of the Brain , 2006 .

[67]  Timothy E. J. Behrens,et al.  Just pretty pictures? What diffusion tractography can add in clinical neuroscience , 2006, Current opinion in neurology.

[68]  Timothy Edward John Behrens,et al.  Connection patterns distinguish 3 regions of human parietal cortex. , 2006, Cerebral cortex.

[69]  Timothy Edward John Behrens,et al.  The evolution of prefrontal inputs to the cortico-pontine system: diffusion imaging evidence from Macaque monkeys and humans. , 2006, Cerebral cortex.

[70]  James R. MacFall,et al.  Dorsolateral Prefrontal Cortex and Anterior Cingulate Cortex White Matter Alterations in Late-Life Depression , 2006, Biological Psychiatry.

[71]  Irene Tracey,et al.  Determining anatomical connectivities between cortical and brainstem pain processing regions in humans: A diffusion tensor imaging study in healthy controls , 2006, Pain.

[72]  Timothy Edward John Behrens,et al.  Between session reproducibility and between subject variability of diffusion MR and tractography measures , 2006, NeuroImage.

[73]  A. Anwander,et al.  Connectivity-Based Parcellation of Broca's Area. , 2006, Cerebral cortex.

[74]  Desmond J. Higham,et al.  Connectivity-based parcellation of human cortex using diffusion MRI: Establishing reproducibility, validity and observer independence in BA 44/45 and SMA/pre-SMA , 2007, NeuroImage.

[75]  David W. McNeal,et al.  Amygdala interconnections with the cingulate motor cortex in the rhesus monkey , 2007, The Journal of comparative neurology.

[76]  Sidney H. Kennedy,et al.  Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. , 2007, The American journal of psychiatry.

[77]  Mark W. Woolrich,et al.  Probabilistic diffusion tractography with multiple fibre orientations: What can we gain? , 2007, NeuroImage.

[78]  M. Glickstein.  Fibre pathways of the brain , 2007 .