The ventral, medial prefrontal cortex and cingulate cortex, the major white matter pathways that connect them (and their links to the basal ganglia) are central parts of the reward/motivation circuit. Dysfunction in these areas is associated with several psychiatric diseases including depression. Fibers from these cortical areas are captured at two surgical targets for treatment resistant depression (anterior cingulotomy and deep brain stimulation of the subgenual cingulate). The goal of this application is to gain insight into the anatomical substrates that underlie human functional connectivity profiles and changes in disease derived from imaging studies. Cortex and basal ganglia are generally organized in parallel functional circuits, yet emerging data indicate that specific subregions also serve as connectional nodes that integrate information processing across functional systems. Our work has focused on how prefrontal cortical regions are anatomically linked through the basal ganglia, to integrate across reward/motivation and cognitive domains. We have recently expanded these studies to examine cortico-cortical connections, particularly, the white matter pathways that connect them. By combining anatomical tracing and diffusion magnetic resonance imaging we are exploring the ability of imaging to replicate fiber pathways.
The aim here is to build on our previous findings combining non-human primate anatomical tracing, non-human primate diffusion magnetic resonance imaging, and human dMRI to identify cortical and basal ganglia areas that anatomically link areas of prefrontal cortex and cingulate cortex. Data will be used to determine the pathways/structures involved at the cingulotomy and subgenual DBS targets.
Aim 1 uses conventional tracing experiments to determine how cingulate and prefrontal cortical terminals and pathways interface.
Aim 2 will determine their pathways through the cingulum, uncinate fasciculus, and corpus callosum, and the ability for diffusion imaging tractography to replicate these connections.
Aim 3 will use the results from Aim 2 to evaluate and segment the cingulum and uncinate fasciculus, and the corpus callosum in healthy human subjects and delineate which connections are likely to pass through the surgical targets, the dorsal anterior cingulate (cingulotomy) and subgenual anterior cingulate (deep brain stimulation).

Public Health Relevance

Depression is a serious, chronic, and debilitating psychiatric illness, with an estimated 350 million people affected worldwide. The World Health Organization has placed depression in the top ten debilitating diseases. This study will examine the anatomical underpinnings of the neural network that underlie changes associated with this disease. This circuit is not limited to depression, but is associated with a range of affective and addictive disorders. The collective proposed studies will generate new hypotheses of how dysfunctions within these brain networks are expressed across diseases and provide insight into network underlying normal behavioral responses.

National Institute of Health (NIH)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Rossi, Andrew
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University of Rochester
School of Medicine & Dentistry
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Haber, Suzanne N; Behrens, Timothy E J (2014) The neural network underlying incentive-based learning: implications for interpreting circuit disruptions in psychiatric disorders. Neuron 83:1019-39
Heilbronner, Sarah R; Haber, Suzanne N (2014) Frontal cortical and subcortical projections provide a basis for segmenting the cingulum bundle: implications for neuroimaging and psychiatric disorders. J Neurosci 34:10041-54
Averbeck, Bruno B; Lehman, Julia; Jacobson, Moriah et al. (2014) Estimates of projection overlap and zones of convergence within frontal-striatal circuits. J Neurosci 34:9497-505
Haber, Suzanne N; Heilbronner, Sarah R (2013) Translational research in OCD: circuitry and mechanisms. Neuropsychopharmacology 38:252-3
Haynes, William I A; Haber, Suzanne N (2013) The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for Basal Ganglia models and deep brain stimulation. J Neurosci 33:4804-14
Haber, Suzanne N; Knutson, Brian (2010) The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35:4-26
Kegeles, Lawrence S; Abi-Dargham, Anissa; Frankle, W Gordon et al. (2010) Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 67:231-9
Ding, Song-Lin; Haber, Suzanne N; Van Hoesen, Gary W (2010) Stratum radiatum of CA2 is an additional target of the perforant path in humans and monkeys. Neuroreport 21:245-9
May, Paul J; McHaffie, John G; Stanford, Terrence R et al. (2009) Tectonigral projections in the primate: a pathway for pre-attentive sensory input to midbrain dopaminergic neurons. Eur J Neurosci 29:575-87
Haber, Suzanne N; Brucker, Justin L (2009) Cognitive and limbic circuits that are affected by deep brain stimulation. Front Biosci 14:1823-34

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