The Subcallosal Cingulate Gyrus in the Context of Major Depression
2010; Elsevier BV; Volume: 69; Issue: 4 Linguagem: Inglês
10.1016/j.biopsych.2010.09.034
ISSN1873-2402
AutoresClement Hamani, Helen S. Mayberg, Scellig Stone, Adrian W. Laxton, Suzanne N. Haber, Andrés M. Lozano,
Tópico(s)Neurological disorders and treatments
ResumoThe subcallosal cingulate gyrus (SCG), including Brodmann area 25 and parts of 24 and 32, is the portion of the cingulum that lies ventral to the corpus callosum. It constitutes an important node in a network that includes cortical structures, the limbic system, thalamus, hypothalamus, and brainstem nuclei. Imaging studies have shown abnormal SCG metabolic activity in patients with depression, a pattern that is reversed by various antidepressant therapies. The involvement of the SCG in mechanisms of depression and its emerging potential role as a surgical target for deep brain stimulation has focused recent interest in this area. We review anatomic and histologic attributes of the SCG and the morphologic and imaging changes observed in depression. Particular attention is given to the regional and downstream structures that could be influenced by the application of deep brain stimulation in this region. The subcallosal cingulate gyrus (SCG), including Brodmann area 25 and parts of 24 and 32, is the portion of the cingulum that lies ventral to the corpus callosum. It constitutes an important node in a network that includes cortical structures, the limbic system, thalamus, hypothalamus, and brainstem nuclei. Imaging studies have shown abnormal SCG metabolic activity in patients with depression, a pattern that is reversed by various antidepressant therapies. The involvement of the SCG in mechanisms of depression and its emerging potential role as a surgical target for deep brain stimulation has focused recent interest in this area. We review anatomic and histologic attributes of the SCG and the morphologic and imaging changes observed in depression. Particular attention is given to the regional and downstream structures that could be influenced by the application of deep brain stimulation in this region. There has been a marked increase in the number of clinical conditions treated with deep brain stimulation (DBS). Among the most promising indications are psychiatric disorders, particularly major depression (1Jimenez F. Velasco F. Salin-Pascual R. Hernandez J.A. Velasco M. Criales J.L. et al.A patient with a resistant major depression disorder treated with deep brain stimulation in the inferior thalamic peduncle.Neurosurgery. 2005; 57 (discussion: 585–593): 585-593Crossref PubMed Scopus (185) Google Scholar, 2Lozano A.M. Mayberg H.S. Giacobbe P. Hamani C. Craddock R.C. Kennedy S.H. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression.Biol Psychiatry. 2008; 64: 461-467Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar, 3Malone Jr, D.A. Dougherty D.D. Rezai A.R. Carpenter L.L. Friehs G.M. 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Hamani C. et al.Deep brain stimulation for treatment-resistant depression.Neuron. 2005; 45: 651-660Abstract Full Text Full Text PDF PubMed Scopus (2837) Google Scholar) based on preliminary imaging data, showing an involvement of this region in the mechanisms of treatment-resistant depression (8Mayberg H.S. Modulating dysfunctional limbic-cortical circuits in depression: Towards development of brain-based algorithms for diagnosis and optimised treatment.Br Med Bull. 2003; 65: 193-207Crossref PubMed Scopus (895) Google Scholar, 9Mayberg H.S. Liotti M. Brannan S.K. McGinnis S. Mahurin R.K. Jerabek P.A. et al.Reciprocal limbic-cortical function and negative mood: Converging PET findings in depression and normal sadness.Am J Psychiatry. 1999; 156: 675-682PubMed Google Scholar). The growing interest in this area (8Mayberg H.S. 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Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression.Biol Psychiatry. 2008; 64: 461-467Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar, 4Mayberg 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: 651-660Abstract Full Text Full Text PDF PubMed Scopus (2837) Google Scholar), warranted a review of histologic and anatomic aspects of the subcallosal cingulum in the context of depression. The cingulate gyrus is an arch-shaped convolution in the medial surface of the cerebral hemisphere. It lies in close relation to the corpus callosum, from which it is separated by the callosal fissure (11Crossman A.R. Cerebral hemisphere.in: Standring S. Gray's Anatomy: The Anatomical Basis of Clinical Practice. 39th ed. Elsevier, Churchill, Livingstone, Edinburgh, London, New York, Oxford, Philadelphia, St Louis, Sidney, Toronto2005: 387-417Google Scholar). It commences below the rostrum, curves around anterior to the genu, extends along the dorsal surface of the body, and finally turns ventrally behind the splenium, where it is connected by a narrow isthmus with the hippocampal gyrus (11Crossman A.R. Cerebral hemisphere.in: Standring S. Gray's Anatomy: The Anatomical Basis of Clinical Practice. 39th ed. Elsevier, Churchill, Livingstone, Edinburgh, London, New York, Oxford, Philadelphia, St Louis, Sidney, Toronto2005: 387-417Google Scholar). It is separated from the medial part of the superior frontal gyrus by the cingulate sulcus, which commonly extends posteriorly into the parietal lobe as the marginal ramus. On the basis of cytoarchitectural characteristics (discussed subsequently), the cingulate gyrus has been classically subdivided in anterior cingulate cortex (ACC), posterior cingulate cortex, and retrosplenial cingulate cortex (12Devinsky O. Morrell M.J. Vogt B.A. Contributions of anterior cingulate cortex to behaviour.Brain. 1995; 118: 279-306Crossref PubMed Scopus (2760) Google Scholar, 13Paus T. Primate anterior cingulate cortex: Where motor control, drive and cognition interface.Nat Rev Neurosci. 2001; 2: 417-424Crossref PubMed Scopus (1367) Google Scholar, 14Vogt B.A. Structural organization of cingulate cortex: Areas, neurons, and somatodendritic transmitter receptors.in: Vogt B. Gabriel M. Neurobiology of the Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Birkhäuser, Boston/Basel/Berlin1993: 19-70Google Scholar). Alternatively, it has been subdivided in four main regions based not only on histologic features but also common afferent and efferent projections (15Vogt B.A. Pain and emotion interactions in subregions of the cingulate gyrus.Nat Rev Neurosci. 2005; 6: 533-544Crossref PubMed Scopus (1326) Google Scholar, 16Vogt B.A. Vogt L. Farber N.B. Bush G. Architecture and neurocytology of monkey cingulate gyrus.J Comp Neurol. 2005; 485: 218-239Crossref PubMed Scopus (174) Google Scholar, 17Vogt B. Cingulate Neurobiology and Disease. Oxford University Press, New York2009Google Scholar). These are the anterior cingulate cortex (further subdivided in subgenual ACC [sACC] and paragenual ACC [pACC] regions), midcingulate cortex, posterior cingulate cortex, and retrosplenial cortex (15Vogt B.A. Pain and emotion interactions in subregions of the cingulate gyrus.Nat Rev Neurosci. 2005; 6: 533-544Crossref PubMed Scopus (1326) Google Scholar, 16Vogt B.A. Vogt L. Farber N.B. Bush G. Architecture and neurocytology of monkey cingulate gyrus.J Comp Neurol. 2005; 485: 218-239Crossref PubMed Scopus (174) Google Scholar). Here we review one subcomponent of the anterior cingulate gyrus, the SCG. This is operationally defined here as the portion of the cingulate gyrus lying ventral to the corpus callosum, from the anterior boundary of the genu to the rostrum. In this context, the terms SCG and subgenual cingulum may be used as synonyms. Comprehensive reviews on the anatomic and physiologic aspects more dorsal regions of the ACC have been published elsewhere (12Devinsky O. Morrell M.J. Vogt B.A. Contributions of anterior cingulate cortex to behaviour.Brain. 1995; 118: 279-306Crossref PubMed Scopus (2760) Google Scholar, 13Paus T. Primate anterior cingulate cortex: Where motor control, drive and cognition interface.Nat Rev Neurosci. 2001; 2: 417-424Crossref PubMed Scopus (1367) Google Scholar, 15Vogt B.A. Pain and emotion interactions in subregions of the cingulate gyrus.Nat Rev Neurosci. 2005; 6: 533-544Crossref PubMed Scopus (1326) Google Scholar). According to Brodmann's classification (14Vogt B.A. Structural organization of cingulate cortex: Areas, neurons, and somatodendritic transmitter receptors.in: Vogt B. Gabriel M. Neurobiology of the Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Birkhäuser, Boston/Basel/Berlin1993: 19-70Google Scholar), the ACC in humans comprises areas 24, 25, 32 (Figure S1 in Supplement 1) and 33 (not represented in the figure; details follow). Regions of the cingulate cortex lying ventral to the corpus callosum include area 25 and the subcallosal portions of 32 and 24 (Figure S1A in Supplement 1). Although the SCG in nonhuman primates also comprises area 25 and portions of 24 and 32, differences exist across species. In contrast to more traditional studies, recent reports in humans suggest that Brodmann's area (BA) 32 may be subdivided in two: a ventral portion located in the vicinity of BA25 and a dorsal portion located anterior and dorsal to the corpus callosum (18Ongur D. Ferry A.T. Price J.L. Architectonic subdivision of the human orbital and medial prefrontal cortex.J Comp Neurol. 2003; 460: 425-449Crossref PubMed Scopus (762) Google Scholar). The former has been suggested as the homologous of the prelimbic BA32 in nonhuman primates. To date, correspondence between cortical regions in nonhuman primates and humans remains controversial. Future investigation is still needed to address this issue. In nonhuman primates and humans, the ACC subdivisions undergo a progressive differentiation (14Vogt B.A. Structural organization of cingulate cortex: Areas, neurons, and somatodendritic transmitter receptors.in: Vogt B. Gabriel M. Neurobiology of the Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Birkhäuser, Boston/Basel/Berlin1993: 19-70Google Scholar, 16Vogt B.A. Vogt L. Farber N.B. Bush G. Architecture and neurocytology of monkey cingulate gyrus.J Comp Neurol. 2005; 485: 218-239Crossref PubMed Scopus (174) Google Scholar, 19Vogt B.A. Nimchinsky E.A. Vogt L.J. Hof P.R. Human cingulate cortex: Surface features, flat maps, and cytoarchitecture.J Comp Neurol. 1995; 359: 490-506Crossref PubMed Scopus (577) Google Scholar, 20Vogt B.A. Pandya D.N. Cingulate cortex of the rhesus monkey II. Cortical afferents.J Comp Neurol. 1987; 262: 271-289Crossref PubMed Scopus (684) Google Scholar, 21Vogt B.A. Pandya D.N. Rosene D.L. Cingulate cortex of the rhesus monkey I. Cytoarchitecture and thalamic afferents.J Comp Neurol. 1987; 262: 256-270Crossref PubMed Scopus (475) Google Scholar). Areas 25 and 32 have poorly differentiated Layers II and III, no layer IV, a prominent Layer V, and a relatively thin Layer VI (14Vogt B.A. Structural organization of cingulate cortex: Areas, neurons, and somatodendritic transmitter receptors.in: Vogt B. Gabriel M. Neurobiology of the Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Birkhäuser, Boston/Basel/Berlin1993: 19-70Google Scholar, 16Vogt B.A. Vogt L. Farber N.B. Bush G. Architecture and neurocytology of monkey cingulate gyrus.J Comp Neurol. 2005; 485: 218-239Crossref PubMed Scopus (174) Google Scholar, 19Vogt B.A. Nimchinsky E.A. Vogt L.J. Hof P.R. Human cingulate cortex: Surface features, flat maps, and cytoarchitecture.J Comp Neurol. 1995; 359: 490-506Crossref PubMed Scopus (577) Google Scholar, 20Vogt B.A. Pandya D.N. Cingulate cortex of the rhesus monkey II. Cortical afferents.J Comp Neurol. 1987; 262: 271-289Crossref PubMed Scopus (684) Google Scholar, 21Vogt B.A. Pandya D.N. Rosene D.L. Cingulate cortex of the rhesus monkey I. Cytoarchitecture and thalamic afferents.J Comp Neurol. 1987; 262: 256-270Crossref PubMed Scopus (475) Google Scholar). Area 24 is also characterized by the absence of Layer IV and relatively poorly differentiated Layers II and III. Its Layer V, however, contains large pyramidal neurons and may be subdivided in Layers Va and Vb. Layer VI is well developed (14Vogt B.A. Structural organization of cingulate cortex: Areas, neurons, and somatodendritic transmitter receptors.in: Vogt B. Gabriel M. Neurobiology of the Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Birkhäuser, Boston/Basel/Berlin1993: 19-70Google Scholar, 16Vogt B.A. Vogt L. Farber N.B. Bush G. Architecture and neurocytology of monkey cingulate gyrus.J Comp Neurol. 2005; 485: 218-239Crossref PubMed Scopus (174) Google Scholar, 19Vogt B.A. Nimchinsky E.A. Vogt L.J. Hof P.R. Human cingulate cortex: Surface features, flat maps, and cytoarchitecture.J Comp Neurol. 1995; 359: 490-506Crossref PubMed Scopus (577) Google Scholar, 20Vogt B.A. Pandya D.N. Cingulate cortex of the rhesus monkey II. Cortical afferents.J Comp Neurol. 1987; 262: 271-289Crossref PubMed Scopus (684) Google Scholar, 21Vogt B.A. Pandya D.N. Rosene D.L. Cingulate cortex of the rhesus monkey I. Cytoarchitecture and thalamic afferents.J Comp Neurol. 1987; 262: 256-270Crossref PubMed Scopus (475) Google Scholar). Cytoarchitectonically, area 24 may be subdivided in three main regions progressively more differentiated from ventral to dorsal. Area 24a borders the indusium griseum and has been described as periallocortex. Area 24b is more differentiated and considered proisocortex. Area 24c lies within the depths of the cingulate sulcus (14Vogt B.A. Structural organization of cingulate cortex: Areas, neurons, and somatodendritic transmitter receptors.in: Vogt B. Gabriel M. Neurobiology of the Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Birkhäuser, Boston/Basel/Berlin1993: 19-70Google Scholar). Area 33 only appears in humans and is located within the depths of the callosal sulcus surrounding the rostrum of the corpus callosum (14Vogt B.A. Structural organization of cingulate cortex: Areas, neurons, and somatodendritic transmitter receptors.in: Vogt B. Gabriel M. Neurobiology of the Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Birkhäuser, Boston/Basel/Berlin1993: 19-70Google Scholar). It contains moderate size cells in Layers II and III and heavily stained neurons in Layer V. In nonhuman primates, the mean number of cells per cubic millimeters in the ACC is approximately 55,000 with no significant differences across BA 25, 24, and 32 (22Gabbott P.L. Bacon S.J. Local circuit neurons in the medial prefrontal cortex (areas 24a,b,c, 25 and 32) in the monkey II. Quantitative areal and laminar distributions.J Comp Neurol. 1996; 364: 609-636Crossref PubMed Scopus (166) Google Scholar, 23Gabbott P.L. Bacon S.J. 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In nonhuman primates and humans, 5% to 12% of ACC neuronal populations express calretinin, parvalbumin, and calbindin (22Gabbott P.L. Bacon S.J. Local circuit neurons in the medial prefrontal cortex (areas 24a,b,c, 25 and 32) in the monkey II. Quantitative areal and laminar distributions.J Comp Neurol. 1996; 364: 609-636Crossref PubMed Scopus (166) Google Scholar, 24Nimchinsky E.A. Vogt B.A. Morrison J.H. Hof P.R. Neurofilament and calcium-binding proteins in the human cingulate cortex.J Comp Neurol. 1997; 384: 597-620Crossref PubMed Scopus (73) Google Scholar). When neurotransmitter receptors are considered, autoradiography studies in postmortem human brains indicate that the ACC is not homogeneous. When compared with neighbor regions, BA25 has low GABAB, high N-methyl-D-aspartate, and high 5-HT1A (serotonin 1 A) receptor densities, more closely resembling the midcingulate cortex (25Palomero-Gallagher N. Vogt B.A. Schleicher A. Mayberg H.S. Zilles K. Receptor architecture of human cingulate cortex: Evaluation of the four-region neurobiological model.Hum Brain Mapp. 2009; 30: 2336-2355Crossref PubMed Scopus (230) Google Scholar). In nonhuman primates, studies on SCG projections have mainly characterized afferents and efferents to and from BA25 (Figure 1). BA32 projections have been predominantly studied in regions anterior and dorsal to the SCG (e.g., prelimbic BA32). Because the prelimbic BA32 in nonhuman primates has been suggested to be homologous to the subgenual BA32 in humans, afferent and efferent projections to and from this region are reported later in the article (26Ongur D. Price J.L. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans.Cereb Cortex. 2000; 10: 206-219Crossref PubMed Scopus (2032) Google Scholar). SCG BA24 projections in nonhuman primates have not been characterized in detail. 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The anatomy of dopamine in monkey and human prefrontal cortex.J Neural Transm Suppl. 1992; 36: 163-177PubMed Google Scholar). Cortical efferents from BA25 in nonhuman primates innervate mainly the temporal pole, agranular insula, orbitofrontal cortex (areas 14c, 14r, and 10 m), and areas 32 and 24 (28Carmichael S.T. Price J.L. Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys.J Comp Neurol. 1996; 371: 179-207Crossref PubMed Scopus (466) Google Scholar). Subcortical projections penetrate the adjacent white matter and innervate rostral and medial aspects of the caudate nucleus, nucleus accumbens (mainly the shell), medial preoptic area, bed nucleus of the stria terminalis, diagonal band of Broca, and lateral septum (45Chiba T. Kayahara T. Nakano K. 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Thereafter, projections from BA25 run caudally through the substantia innominata to innervate the amygdala and parts of the hypothalamus (45Chiba T. Kayahara T. Nakano K. Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata.Brain Res. 2001; 888: 83-101Crossref PubMed Scopus (212) Google Scholar, 46Freedman L.J. Insel T.R. Smith Y. Subcortical projections of area 25 (subgenual cortex) of the macaque monkey.J Comp Neurol. 2000; 421: 172-188Crossref PubMed Scopus (224) Google Scholar). Within the amygdala, axons terminate mainly in the intercalated nuclei and parvocellular portion of the basal nucleus. In addition, the intermediate nucleus, magnocellular part of the basal nucleus, periamygdaloid cortex, and, to a lesser extent, the lateral and central nuclei also receive projections from BA25 (45Chiba T. Kayahara T. Nakano K. Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata.Brain Res. 2001; 888: 83-101Crossref PubMed Scopus (212) Google Scholar, 46Freedman L.J. Insel T.R. Smith Y. Subcortical projections of area 25 (subgenual cortex) of the macaque monkey.J Comp Neurol. 2000; 421: 172-188Crossref PubMed Scopus (224) Google Scholar). In nonhuman primates, efferents to the thalamus primarily innervate the magnocellular division of MD, PT, paraventricular nucleus (PV), and Re (40Hsu D.T. Price J.L. Midline and intralaminar thalamic connections with the orbital and medial prefrontal networks in macaque monkeys.J Comp Neurol. 2007; 504: 89-111Crossref PubMed Scopus (72) Google Scholar, 45Chiba T. Kayahara T. Nakano K. Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata.Brain Res. 2001; 888: 83-101Crossref PubMed Scopus (212) Google Scholar, 46Freedman L.J. Insel T.R. Smith Y. Subcortical projections of area 25 (subgenual cortex) of the macaque monkey.J Comp Neurol. 2000; 421: 172-188Crossref PubMed Scopus (224) Google Scholar), but also the reticular, interanteromedial, central medial, parafascicular, and the limitans nuclei (45Chiba T. Kayahara T. Nakano K. Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata.Brain Res. 2001; 888: 83-101Crossref PubMed Scopus (212) Google Scholar, 46Freedman L.J. Insel T.R. Smith Y. Subcortical projections of area 25 (subgenual cortex) of the macaque monkey.J Comp Neurol. 2000; 421: 172-188Crossref PubMed Scopus (224) Google Scholar). In the hypothalamus, fibers from BA25 innervate the medial preoptic area (45Chiba T. Kayahara T. Nakano K. Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata.Brain Res. 2001; 888: 83-
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