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Thesis defense
1. Sex Differences in the
Relationship Between
Adolescent Brain Activity
and Depressive
Symptoms
Chase Antonacci
Philosophy-Neuroscience-Psychology
2. (1) Ferrari, Alize J., et al. “Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the
Global Burden of Disease Study 2010.” PLoS Medicine, vol. 10, no. 11, 2013,
doi:10.1371/journal.pmed.1001547.
(1)
• 3rd leading cause of disease burden
Ø 66 million DALYs
Ø Prevalence
Ø Suicide
• Adolescence
• Genes + Environment à Depression
• Risk & Resiliency
Major Depressive Disorder
3. (2)
• 3rd leading cause of disease burden
Ø 66 million DALYs
Ø Prevalence
Ø Suicide
• Adolescence
• Genes + Environment à Depression
• Risk & Resiliency
(2) Noorden, M. S., Minkenberg, S. E., Giltay, E. J., Hollander-Gijsman, M. E., Rood, Y. R., Wee, N.
J., & Zitman, F. G. (2010). Pre-adult versus adult onset major depressive disorder in a naturalistic
patient sample: The Leiden Routine Outcome Monitoring Study. Psychological Medicine, 41(07),
1407-1417. doi:10.1017/s0033291710002199
Major Depressive Disorder
4. Biology EnvironmentMDD
• 3rd leading cause of disease burden
Ø 66 million DALYs
Ø Prevalence
Ø Suicide
• Adolescence
• Genes + Environment à Depression
• Risk & Resiliency
Major Depressive Disorder
5. Sex Differences in MDD
• Factors impacting risk:
Ø Age
Ø Marital Status
Ø SES
Ø Sex
• 2x globally
• Adolescence
Ø Why? Can we predict?
(3) Hankin BL, Abramson LY, Moffitt TE, McGee R, Silva PA, Angell KE. Development of depression from
preadolescence to young adulthood: emerging gender differences in a 10-year longitudinal study. J Abnorm
Psychol. 1998;107:128-140.
(3)
6. Sex Differences in MDD
• Functional Differences – Adults
• Emotional Responsivity
• Emotion Regulation – Cog
Reappraisal
Ø Men more efficient?
Ø Women upregulate positive?
(4)
(4) McRae, K., Ochsner, K. N., Mauss, I. B., Gabrieli, J. J. D., & Gross, J. J. (2008). Gender
Differences in Emotion Regulation: An fMRI Study of Cognitive Reappraisal. Group Processes
& Intergroup Relations : GPIR, 11(2), 143–162. https://doi.org/10.1177/1368430207088035
7. Emotion Regulation
• ER = Conscious & unconscious cognitive
and behavioral processes by which emotions
are modulated and controlled
• ER Schema
• Adaptive: ex. Cognitive Reappraisal
Ø Adaptive Behavioral Response
• Maladaptive: ex. Suppression
Ø Risk for depressive symptomatology
8. Emotion Regulation
• ER key for interpersonal relationships5
Ø Prosocial tendencies
Ø Interpersonal sensitivity
• Better psychosocial outcomes6
Ø Life satisfaction
Ø Social support perception
Ø Positive affect
• Social Development – tripartite
model7
Ø Parenting styles à differential
activation
(5) Lopes, P. N., Salovey, P., Côté, S., & Beers, M. (2005). Emotion Regulation Abilities and the
Quality of Social Interaction. Emotion, 5(1), 113–118. https://doi.org/10.1037/1528-
3542.5.1.113
(6) Verzeletti, C., Zammuner, V. L., Galli, C., & Agnoli, S. (2016). Emotion regulation strategies
and psychosocial well-being in adolescence. Cogent Psychology, 3(1).
(7) Morris, A. S., Criss, M. M., Silk, J. S., & Houltberg, B. J. (2017). The Impact of Parenting on
Emotion Regulation During Childhood and Adolescence. Child Development Perspectives,
11(4), 233–238. https://doi.org/10.1111/cdep.12238
9. ER & Depression
• Depression = Disorder of Impaired Emotion Regulation
Ø Difficulty in ER = “core vulnerability” in adolescents
Ø Inhibit processing of negative thought & feelings
• ER in adjustment problems & depression development
• Joorman & Gotlib8: MDD à Lack of inhibitory control for
negative emotions à rumination & decreased reappraisal
Ø Maladaptive strategies ~ increased depressive symptoms
(8) Joormann, J., & Gotlib, I. H. (2010). Emotion Regulation in Depression: Relation to Cognitive Inhibition.
Cognition & Emotion, 24(2), 281 298. https://doi.org/10.1080/02699930903407948
10. Localizing ER
• ER processes recruit cog control regions
to modulate semantic representations
• Lateral PFC, amygdala, IFG, insula,
temporal/parietal cortices, ACC, PCC
Ø Processing vs. metabolic demand?
• Network!
Ø Different strategies à different
connectivity pathways
o Mindfulness: regulate amygdala via mPFC
o Suppression: regulate amygdala via dlPFC
Brain Regions Implicated in Emotion Regulation
Explicit ER Implicit ER
(9) Brain picture: Goldin, P. R., Mcrae, K., Ramel, W., & Gross, J. J. (2008). The Neural Bases of Emotion Regulation:
Reappraisal and Suppression of Negative Emotion. Biological Psychiatry, 63(6), 577-586. doi:10.1016/j.biopsych.2007.05.031
(9)
11. ER Network
• MDD = network-wide dysfunction
Ø Orbitofrontal cortex + medial PFC
• Gotlib & Joormann10: Emotional Faces
(10) Gotlib, I. H., & Joormann, J. (2010). Cognition and depression: Current status
and future directions. Annual Review of Clinical Psychology, 6, 285–312.
(11) Kohn, N., Eickhoff, S. B., Scheller, M., Laird, A. R., Fox, P. T., & Habel, U.
(2014). Neural network of cognitive emotion regulation – an ALE meta-
analysis and MACM analysis. NeuroImage, 87, 345-55.
(11)
12. Social Theory
• Nolen-Hoeksema8: Social factors influence vulnerability
• Adolescence: realization of social capital disparity
Ø Greater trauma: sexual abuse, poverty, harassment, constrained choices
Ø Adulthood: domestic/occupational discrimination
• Developmental disturbance à biological disruptions
Ø Chronic stress & HPA axis
Ø Elevated urinary cortisol & failure to suppress endogenous cortisol
Ø Compromised stress response system
Ø Neurocircuitry disruption à increased vulnerability
• Mechanistically similar to ACEs13?
(12) Nolen-Hoeksema, S. (2001a). Gender Differences in Depression. Current
Directions in Psychological Science, 10(5), 173–176.
(13) Luby, J. L., Barch, D., Whalen, D., Tillman, R., & Belden, A. (2017). Association
Between Early Life Adversity and Risk for Poor Emotional and Physical Health in
Adolescence: A Putative Mechanistic Neurodevelopmental Pathway. JAMA Pediatrics,
171(12), 1168–1175.
13. Biological Theory
• Innate biological differences
• Corticotrophin releasing factor &
glucocorticoids
• Female rats: higher sensitivity to low
levels CRF & less adaptation to high
• Genetic heritability
• Systematic dysregulation
(14)
(14) Bangasser, D. A. (2013). Sex differences in stress-related receptors: “micro”
differences with “macro” implications for mood and anxiety disorders. Biology of Sex
Differences, 4(1), 2. https://doi.org/10.1186/2042-6410-4-2
15. Current Study
• Objective: examine neurobiological differences between boys and girls
underlying the differential in depressive symptomatology
• What rather than why
• Prediction?
• Hypothesis:
Ø Girls will exhibit lower activation relative to boys in key ER regions
including the amygdala, dlPFC, vmPFC, ACC, PCC, and insula
Ø Girls will exhibit higher rates of depressive symptoms (MFQ) and higher
difficulty in emotion regulation (DERS)
19. Methods
Analyses
• Behavioral: group differences in behavioral measures
• Neuroimaging:
Ø Pre-processing: Slice-time correction, motion correction, spatial
normalization to Talairach & Tournoux (1988), early TR exclusion, smoothing with
6mm FWHM Gaussian kernel
Ø Modeling: ‘costly error’ – ‘both correct’; nuisance regressors
Ø Group Analysis: task effects, MFQ, DERS
Ø Masking: 70% whole brain average, ROI masks to a priori selected regions
Ø Multiple comparisons: voxelwise p<0.005, a cluster-size threshold of p<0.05
20. Methods
Terminology
• “Sex” versus “gender”
• Surveyed “sex” of participants
• Biology-based vs. socially-determined
influences terminology
• Consistent with literature
• “Sex” as neutral interpretation
Ø Don’t defend implications
21. Results
Behavioral Data
Table 1: Descriptive and inferential statistics for DERS & MFQ Self-Report Measures. No group-level differences appeared on self-report scores between
boys and girls. The two measures that did exhibit group-level differences (APQ-Mom Involvement and SCARED-Social Anxiety Disorder) were not included in
this table given that they were not measures of interest in the present study.
Self-Report Measures
22. Results
Main Effects
• Strong task effects
• Activation following a
parent’s costly error
• Large clusters in ER
regions
• Cluster threshold = 378
• No main effects of
MFQ/DERS
Task Effects
23. Results
MFQ
• Boys & girls differed in the relationship between MFQ score & brain activity
in both the PCC and dlPFc bilaterally
• Boys exhibited greater activation on average in response to a costly error
made by a parent
24. Results
MFQ – PCC
• Opposite activation
trends
• Boys: higher MFQ scores
associated with
upregulation of the PCC
• Girls: downregulation of
the PCC associated with
greater MFQ scores
• Recruitment efficacy?
MFQ: Posterior Cingulate Cortex
25. Results
MFQ – dlPFC
• Opposite activation
trends
• Boys: higher MFQ scores
associated with
upregulation of the
dlPFC
• Girls: downregulation of
the dlPFC associated
with greater MFQ scores
• Recruitment efficacy?
MFQ: Dorsolateral Prefrontal Cortex
26. Results
DERS
• Boys & girls differed in the relationship
between DERS score & brain activity in both the right PCC
• Opposite activation trends – analogous to MFQ
DERS: Right Posterior Cingulate
27. Implications
• Observed difference between brain activity & both depressive symptoms
and emotion regulation skill between adolescent boys & girls – opposite
trends in activation
• Potential neurobiological mechanism underlying risk differential
• May experience similar levels of depressive symptoms à progression of
MDD more prevalent due to differences in ER networks
• Alternative interpretations?
• Adolescence key for cementing ER strategy à risk across lifespan
(10) Yap, B. H., Allen, N. B., & Ladouceur, C. D. (2008). Maternal Socialization of Positive Affect:
The Impact of Invalidation on Adolescent Emotion Regulation and Depressive Symptomatology -
Yap - 2008 - Child Development - Wiley Online Library. Child Development, 79 (5), 1415–1341.
(11) Golkar, A., Lonsdorf, T. B., Olsson, A., Lindstrom, K. M., Berrebi, J., Fransson, P., … Öhman, A.
(2012). Distinct contributions of the dorsolateral prefrontal and orbitofrontal cortex during emotion
regulation. PloS One, 7(11), e48107. https://doi.org/10.1371/journal.pone.0048107
28. Strengths & Weaknesses
Strengths:
• One of the first to examine functional differences in adolescent populations
relating to sex differences in depression
• Social engagement task; not conscious cognitive manipulation of ER
Weaknesses:
• Longitudinal data
• Small sample size & restricted range
29. Future Directions
• Longitudinal investigation – are these results predictive of MDD onset?
• Can patterns in pre-depressive brain activity be used to identify those
at risk and enable earlier/more effective intervention?
• Directional investigation – is up/downregulation a ‘product’ or ‘driver’
of depressive symptomatology
• ER development – how does parent/peer social environment shape
ER networks & interact with depression?
• Can models approximate an ER index (similar to ACE score) to predict risk
30. Summary
• Causal etiology for sex disparity in MDD remains unknown
• But, have potential neurobiological signature underpinning for
this difference
• Centered at key point in the developmental timeline
• Boys appear to be upregulating ER regions when faced with an socially-
situated, emotionally-vexing stimulus in comparison to girls
Ø Potentially enables boys to better process/cope with negative emotions
and develop healthy ER strategies, enhancing resiliency to MDD
• But perhaps not. Complicated system.
32. Acknowledgements
Laureate Institute for Brain Research
• Amanda Morris, Ph.D.
• Kara Kerr, Ph.D.
• Kelly Cosgrove
• Erin Ratliff
• Danielle Deville
• Kai Ping Burrows, Ph.D.
• Kyle Simmons, Ph.D.
• Jerzy Bodurka, Ph.D.
Washington University in St. Louis
• Deanna Barch, Ph.D.
• Austin Andrews, Ph.D.
• Department of Philosophy-
Neuroscience-Psychology
Funding
• National Institutes of Health
Centers for Biomedical Research Excellence
(COBRE): P20GM121312
