The study examined differences in brain activity and its relationship to depressive symptoms between adolescent boys and girls. It found that boys and girls showed opposite patterns of activation in the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (dlPFC) that correlated with their reported depressive symptoms and difficulties with emotion regulation. Specifically, boys showed increased activation in these areas associated with higher symptoms, while girls showed decreased activation. This suggests a potential neurobiological mechanism underlying differences in depression risk between adolescent males and females.

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

14. Etiology
Biology Environment
Risk
&
Resiliency

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)

16. Methods
Participants & Procedure
• Dyadic Inter-Brain Signaling Project
• fMRI hyperscanning
• 29 mother-child dyads
• Adolescent ages 14-16
(M = 14.8)
• Healthy sample (MINI 7.0)
• Visit 1: Screening & Assessment
• Visit 2: Scan
TEAM
Task
fMRI
Hyperscanning

17. Methods
Procedure
• MFQ: Mood & Feelings Questionnaire
Ø 33 questions, scored from 0-66
Ø Assess for depressive symptoms
Ø 0 – 2 Likert scale: “not true,” “somewhat true,” or “true”
• DERS: Difficulties in Emotion Regulation Scale
Ø 36 questions, scored from 36-180
Ø Six facets of ER
Ø 1-5 Likert scale: “almost never”…”almost always”

18. Methods
TEAM Task
Testing Emotional Attachment & Mutuality (TEAM) Task
Adolescents Activation Profile

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.

31. Long-Term Goals

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