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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2019)

Using cross-sectional structural magnetic resonance imaging (MRI) data from six cohorts originating from three sites, this study investigated the cortical morphometric trajectories of six insular subregions of individuals with major depressive disorder (MDD) compared to healthy individuals across the lifespan to better understand the neurodevelopmental and neurodegeneration aspects of MDD. The insula is a centrally located region of the brain responsible for emotional regulation and awareness and has been implicated in many psychiatric disorders including MDD. Participants across all sites included in this study totaled 203 individuals with current MDD (F=137, M=66) and 215 healthy controls (F=110, M=105). T1-weighted magnetic resonance (MR) images from each cohort were registered and segmented using Advanced Normalization Tools (ANTs) and a 3D probabilistic atlas of the human brain, including the following insular regions: posterior long gyrus, anterior long gyrus, anterior short gyrus, middle short gyrus, posterior short gyrus, and anterior inferior cortex. In addition, we examined the amygdala, anterior cingulate gyrus, lateral occipital cortex, cuneus, subgenual cortex, and lateral orbitofrontal cortex. The outputs were then standardized and harmonized to adjust site effects in morphometric measurements while preserving biological variation due to age, sex, relative intracranial volume, and diagnosis. We hypothesized that the relationships among morphometric measures and age are dynamic across the lifespan and influenced by MDD. For each region of interest considered in this study, linear, quadratic, and cubic models were tested to model morphometry and age association first within each group separately and then tested for group-age interaction. Our statistical analyses indicate that the volumes of all insular subregions in the left hemisphere, as well as the right anterior short gyrus, middle short gyrus and anterior long gyrus, exhibited a significant age-associated difference between the control and MDD groups. Furthermore, the group-age interaction revealed that these deviations were particularly significant for 60-79 years of age, indicating co-morbidity of depression with neurodegeneration. Most non-insular regions showed significant differences between groups, but association with age was less robust. Results for the surface area analysis were less conclusive. Further analysis of other metrics related to neurodevelopment (i.e. cortical thickness) will better inform this facet of the disease.

    Cover page: Lifespan Changes of the Human Insula in Major Depression
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2022)

    Background

    Major depressive disorder (MDD) is a complex disorder that affects nearly 264 million people worldwide. Structural brain abnormalities in multiple neuroanatomical networks have been implicated in the etiology of MDD, but the degree to which MDD affects brain structure during early to late adulthood is unclear.

    Methods

    We examined morphometry of brain regions commonly implicated in MDD, including the amygdala, hippocampus, anterior cingulate gyrus, lateral orbitofrontal gyrus, subgenual cortex, and insular cortex subregions, from early to late adulthood. Harmonized measures for gray matter (GM) volume and cortical thickness of each region were estimated cross-sectionally for 305 healthy controls (CTLs) and 247 individuals with MDD (MDDs), collated from four research cohorts. We modeled the nonlinear associations of age with GM volume and cortical thickness using generalized additive modeling and tested for age-dependent group differences.

    Results

    Overall, all investigated regions exhibited smaller GM volume and thinner cortical measures with increasing age. Compared to age matched CTLs, MDDs had thicker cortices and greater GM volume from early adulthood until early middle age (average 35 years), but thinner cortices and smaller GM volume during and after middle age in the lateral orbital gyrus and all insular subregions. Deviations of the MDD and CTL models for both GM volume and cortical thickness in these regions started as early as age 18.

    Conclusions

    The analyses revealed that brain morphometry differences between MDDs and CTLs are dependent on age and brain region. The significant age-by-group interactions in the lateral orbital frontal gyrus and insular subregions make these regions potential targets for future longitudinal studies of MDD.
      Cover page: Age-dependent brain morphometry in Major Depressive disorder
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2021)
      Major depressive disorder (MDD) is a primary psychiatric illness worldwide; there is a dearth of new mechanistic models for the development of better therapeutic strategies. Although we continue to discover individual biological factors, a major challenge is the identification of integrated, multidimensional traits underlying the complex heterogeneity of depression and treatment outcomes. Here, we set out to ascertain the emergence of the novel mitochondrial mediator of epigenetic function acetyl-L-carnitine (LAC) in relation to previously described individual predictors of antidepressant responses to the insulin-sensitizing agent pioglitazone. Herein, we report that i) subjects with MDD and shorter leukocyte telomere length (LTL) show decreased levels of LAC, increased BMI, and a history of specific types of childhood trauma; and that ii) these multidimensional factors spanning mitochondrial metabolism, cellular aging, metabolic function, and childhood trauma provide more detailed signatures to predict longitudinal changes in depression severity in response to pioglitazone than individual factors. The findings of multidimensional signatures involved in the pathophysiology of depression and their role in predicting treatment outcomes provide a starting point for the development of a mechanistic framework linking biological networks and environmental factors to clinical outcomes in pursuit of personalized medicine strategies to effectively treat MDD.
        Cover page: Multidimensional predictors of antidepressant responses: Integrating mitochondrial, genetic, metabolic and environmental factors with clinical outcomes.
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