I graduated with a B.S. in both genetics and psychology and earned a Ph.D. in psychiatric genetics. My Ph.D. work was based on the principle that temperament and neurocognitive function could be used as intermediate traits or endophenotypes in order to facilitate the identification of genetic variants predisposing to bipola disorder. Subsequently, I completed a post-doctoral fellowship under the mentorship of Dr. Drevets at the NIMH where I focused on PET and MRI with a view to leveraging these techniques for genetic analyses. I am currently an assistant professor at the Laureate Institute for Brain Research (LIBR) focusing on bridging the gap between immune dysfunction and neuroimaging abnormalities in major depressive disorder (MDD). Inflammation is hypothesized to contribute to depression by altering the breakdown of tryptophan (TRP), the precursor of serotonin, reducing serotonin levels and increasing the synthesis of kynurenine (KYN) and neurotoxic KYN metabolites, such as 3-hydroxykynurenine (3HK), and quinolinic acid (QUIN). One of the pro-inflammatory cytokines that drives this metabolic shunt towards KYN synthesis is interleukin 6 (IL6), an effect that is partly countered by the anti-inflammatory cytokine, interleuin 10 (IL10).
My aim for the proposed K01 is to examine the association between the plasma concentrations of IL6, IL10, TRP/KYN metabolites, and three neurophysiological correlates of MDD: (a) the abnormal pattern of hemodynamic response in the amygdala, hippocampus, and perigenual ACC to emotionally-valenced faces, (b) reductions in hippocampal volume, and (c) reductions in volume and/or thickness of the perigenual anterior cingulate cortex (ACC). A post-hoc analysis with additional, commonly measured cytokines: IN?, IL2, IL4, IL5, IL1?, IL8, TNF?, and IL12p70 (hereafter bead array: BA cytokines) will also be conducted. A reduction in amygdala volume will also be assessed post-hoc. Sixty MDD patients and 60 healthy controls (HCs) will be recruited. Plasma concentrations of IL6, IL10, and BA cytokines will be measured using cytokine bead arrays, while measurements of TRP, KYN, and 3HK will be obtained with high performance liquid chromatography (HPLC). Imaging will be conducted on a GE MR750 3T scanner with a 32-channel coil. Functional images (voxel size=2.5mm x 2.5mm x 2.9mm) will be coregistered to an anatomical image (voxel size =0.86mm x 0.86mm x 0.9mm), which will in turn be used to obtain FreeSurfer-derived volumetric and cortical thickness measurements. In addition, high resolution T1 and T2 images (0.47mm x 0.47mm x 2.0mm) will be used for manual segmentation of the amygdala and subregions of the hippocampus and ACC. Pilot data obtained in 6 matched pairs of MDD patients and HCs support several of our hypotheses: (a). The MDD patients had smaller hippocampi, thinner ACCs, and showed greater amygdala, hippocampal and ventromedial PFC activity in response to masked sad vs happy faces than HCs. (b). MDD patients showed higher levels of IL6 and 3HK, but lower levels of IL10 than HCs. (c). Higher concentrations of IL6 were associated with lower hippocampal and amygdala volume, and a greater left perigenual ACC response to masked sad vs happy faces. Conversely, IL10 concentrations appeared positively correlated with hippocampal volume and ACC thickness. (d). Higher levels of 3-HK were associated with reduced amygdala volume and ACC thickness, and a greater right hippocampal response to masked sad vs happy faces. (e). The TRP-KYN ratio was inversely associated with a reduced right amygdala response to sad vs happy faces. This project may constitute a preliminary step towards elucidating one of the pathophysiological mechanisms of mood disorders, potentially facilitating the development of next-generation antidepressant medications that target this pathway, as well as non-invasive immunological biomarkers for identifying patients with an "inflammatory" subtype of MDD. This K01 application is designed to provide me with the training needed to work at the interface of the neuroimmunology and neuroimaging fields, thus allowing me to achieve my long-term career goal of providing intellectual insight into the immunological basis of mood disorders, thereby promoting the development of novel treatments. (a). I will develop a working knowledge of immunological function and understand the impact of cytokines and TRP-KYN metabolism on neuroinflammatory processes in the CNS. This training will take place under the mentorship of Drs. Dantzer and Teague, and will incorporate visits to both labs to learn HPLC and cytokine array techniques, respectively. (b). I will become proficient in fMRI techniques and data analysis under the mentorship of Drs. Bellgowan and Drevets. "Hands-on" work with Dr. Bellgowan will focus on experimental design and data processing using AFNI while Dr. Drevets will emphasize methodological issues arising within the context of the literature. In addition, I will attend the AFNI "bootcamp" and FreeSurfer training course in years 2 and 3 of my training, respectively. (c) Under the mentorship of Dr. Drevets, I will deepen my knowledge of the neurobiology of mood disorders and will obtain further training in neuroanatomy, enabling me to better interpret imaging results reported in the literature and facilitating the manual segmentation of hippocampal and ACC subregions. (d) I will obtain further training in research ethics and develop important "softer skills" such as conflict management, and the recruitment, supervision, and mentoring of staff and students.
This application seeks to identify the biological pathway through which inflammation affects brain structure and function in major depressive disorder, thereby unmasking a series of molecular targets for the development of next-generation antidepressant medications.
|Savitz, Jonathan; Drevets, Wayne C; Smith, Chelsey M et al. (2015) Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder. Neuropsychopharmacology 40:463-71|