Frontal Cortical and Subcortical Projections Provide a Basis for Segmenting the Cingulum Bundle: Implications for Neuroimaging and Psychiatric Disorders

The cingulum bundle (CB) is one of the brain's major white matter pathways, linking regions associated with executive function, decision-making, and emotion. Neuroimaging has revealed that abnormalities in particular locations within the CB are associated with specific psychiatric disorders, including depression and bipolar disorder. However, the fibers using each portion of the CB remain unknown. In this study, we used anatomical tract-tracing in nonhuman primates (Macaca nemestrina, Macaca fascicularis, Macaca mulatta) to examine the organization of specific cingulate, noncingulate frontal, and subcortical pathways through the CB. The goals were as follows: (1) to determine connections that use the CB, (2) to establish through which parts of the CB these fibers travel, and (3) to relate the CB fiber pathways to the portions of the CB identified in humans as neurosurgical targets for amelioration of psychiatric disorders. Results indicate that cingulate, noncingulate frontal, and subcortical fibers all travel through the CB to reach both cingulate and noncingulate targets. However, many brain regions send projections through only part, not all, of the CB. For example, amygdala fibers are not present in the caudal portion of the dorsal CB. These results allow segmentation of the CB into four unique zones. We identify the specific connections that are abnormal in psychiatric disorders and affected by neurosurgical interventions, such as deep brain stimulation and cingulotomy.

[1]  Manzar Ashtari,et al.  White matter abnormalities in obsessive-compulsive disorder: a diffusion tensor imaging study. , 2005, Archives of general psychiatry.

[2]  Krystof S. Bankiewicz,et al.  Striatal volume differences between non-human and human primates , 2009, Journal of Neuroscience Methods.

[3]  Sabine Landau,et al.  Evidence for orbitofrontal pathology in bipolar disorder and major depression, but not in schizophrenia. , 2005, Bipolar disorders.

[4]  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.

[5]  C. S. S.,et al.  The Comparative Anatomy of the Nervous System of Vertebrates, including Man , 1937, Nature.

[6]  F. Mettler.  Corticifugal fiber connections of the cortex of Macaca Mullatta. The frontal region , 1935 .

[7]  Derek K. Jones,et al.  Cingulum White Matter in Young Women at Risk of Depression: The Effect of Family History and Anhedonia , 2012, Biological Psychiatry.

[8]  D. Pandya,et al.  Some observations on the course and composition of the cingulum bundle in the rhesus monkey , 1984, The Journal of comparative neurology.

[9]  M. Thase,et al.  Increased Amygdala and Decreased Dorsolateral Prefrontal BOLD Responses in Unipolar Depression: Related and Independent Features , 2007, Biological Psychiatry.

[10]  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.

[11]  M. Mintun,et al.  Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus , 2010, Proceedings of the National Academy of Sciences.

[12]  M. Sam Eljamel,et al.  Anterior Cingulotomy for Major Depression: Clinical Outcome and Relationship to Lesion Characteristics , 2008, Biological Psychiatry.

[13]  J. Dejerine.  Anatomie des centres nerveux , 1895 .

[14]  F. A. Geneser-Jensen.  Distribution of acetyl cholinesterase in the hippocampal region of the guinea pig , 2004, Zeitschrift für Zellforschung und Mikroskopische Anatomie.

[15]  S. Rauch,et al.  Cingulotomy for intractable obsessive-compulsive disorder : prospective long-term follow-up of 18 patients , 1995 .

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

[17]  Do-Un Jeong,et al.  Asymmetrically Altered Integrity of Cingulum Bundle in Posttraumatic Stress Disorder , 2007, Neuropsychobiology.

[18]  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.

[19]  S. Haber,et al.  The organization of the descending ventral pallidal projections in the monkey , 1993, The Journal of comparative neurology.

[20]  S. Rauch,et al.  Invasive Circuitry-Based Neurotherapeutics: Stereotactic Ablation and Deep Brain Stimulation for OCD , 2010, Neuropsychopharmacology.

[21]  Victoria Arango,et al.  Volumetric Analysis of the Prefrontal Cortex, Amygdala, and Hippocampus in Major Depression , 2004, Neuropsychopharmacology.

[22]  Finn A. GENnS.  Distribution of Acetyl Cholinesterase in the Hippocampal Region of the Guinea Pig , 1972 .

[23]  Timothy E. J. Behrens,et al.  Human and Monkey Ventral Prefrontal Fibers Use the Same Organizational Principles to Reach Their Targets: Tracing versus Tractography , 2013, The Journal of Neuroscience.

[24]  Mario Dzemidzic,et al.  Resting state corticolimbic connectivity abnormalities in unmedicated bipolar disorder and unipolar depression , 2009, Psychiatry Research: Neuroimaging.

[25]  D. Pandya,et al.  Efferent Association Pathways from the Rostral Prefrontal Cortex in the Macaque Monkey , 2007, The Journal of Neuroscience.

[26]  P. Goldman-Rakic,et al.  Characterization of the dopaminergic innervation of the primate frontal cortex using a dopamine-specific antibody. , 1993, Cerebral cortex.

[27]  C. McIntyre,et al.  Tractography-Activation Models Applied to Subcallosal Cingulate Deep Brain Stimulation , 2013, Brain Stimulation.

[28]  A. Lozano,et al.  Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression , 2008, Biological Psychiatry.

[29]  R. Luján.  Fiber Pathways of the Brain, J.D. Schmahmann, D.N. Pandya (Eds.). Oxford University Press (2006), ISBN: 0-19-510423-4 , 2008 .

[30]  P. Yakovlev,et al.  Limbic nuclei of thalamus and connections of limbic cortex. III. Corticocortical connections of the anterior cingulate gyrus, the cingulum, and the subcallosal bundle in monkey. , 1961, Archives of neurology.

[31]  Timothy Edward John Behrens,et al.  Cerebral Cortex doi:10.1093/cercor/bhm167 Anatomical Connectivity of the Subgenual Cingulate Region Targeted with Deep Brain Stimulation for Treatment-Resistant Depression , 2007 .

[32]  Maolin Qiu,et al.  Abnormal anterior cingulum integrity in bipolar disorder determined through diffusion tensor imaging , 2008, British Journal of Psychiatry.

[33]  Suzanne N Haber,et al.  Rules Ventral Prefrontal Cortical Axons Use to Reach Their Targets: Implications for Diffusion Tensor Imaging Tractography and Deep Brain Stimulation for Psychiatric Illness , 2011, The Journal of Neuroscience.

[34]  P. Goldman-Rakic,et al.  Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey , 1984, Neuroscience.

[35]  Clement Hamani,et al.  Deep brain stimulation of the subcallosal cingulate gyrus for depression: anatomical location of active contacts in clinical responders and a suggested guideline for targeting. , 2009, Journal of neurosurgery.