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Early life stress, FK506 binding protein 5 gene (FKBP5) methylation, and inhibition-related prefrontal function: A prospective longitudinal study

Published online by Cambridge University Press:  22 November 2017

Madeline B. Harms
Affiliation:
University of Wisconsin–Madison
Rasmus Birn
Affiliation:
University of Wisconsin–Madison
Nadine Provencal
Affiliation:
Max Planck Institute of Psychiatry
Tobias Wiechmann
Affiliation:
Max Planck Institute of Psychiatry
Elisabeth B. Binder
Affiliation:
Max Planck Institute of Psychiatry
Sebastian W. Giakas
Affiliation:
University of Wisconsin–Madison
Barbara J. Roeber
Affiliation:
University of Wisconsin–Madison
Seth D. Pollak*
Affiliation:
University of Wisconsin–Madison
*
Address correspondence and reprint requests to: Seth D. Pollak, Waisman Center, University of Wisconsin–Madison, 1500 Highland Avenue, Madison, WI 53705-2280; E-mail: seth.pollak@wisc.edu.

Abstract

Individuals who have experienced high levels of childhood stress are at increased risk for a wide range of behavioral problems that persist into adulthood, yet the neurobiological and molecular mechanisms underlying these associations remain poorly understood. Many of the difficulties observed in stress-exposed children involve problems with learning and inhibitory control. This experiment was designed to test individuals' ability to learn to inhibit responding during a laboratory task. To do so, we measured stress exposure among a community sample of school-aged children, and then followed these children for a decade. Those from the highest and lowest quintiles of childhood stress exposure were invited to return to our laboratory as young adults. At that time, we reassessed their life stress exposure, acquired functional magnetic resonance imaging data during an inhibitory control task, and assayed these individuals' levels of methylation in the FK506 binding protein 5 (FKBP5) gene. We found that individuals who experienced high levels of stress in childhood showed less differentiation in the dorsolateral prefrontal cortex between error and correct trials during inhibition. This effect was associated only with childhood stress exposure and not by current levels of stress in adulthood. In addition, FKBP5 methylation mediated the association between early life stress and inhibition-related prefrontal activity. These findings are discussed in terms of using multiple levels of analyses to understand the ways in which adversity in early development may affect adult behavioral adaptation.

Type
Special Issue Articles
Copyright
Copyright © Cambridge University Press 2017 

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Footnotes

This work was supported by National Institute of Mental Health Grant MH61285 (to S.D.P.) and Waisman Center Intellectual & Developmental Disabilities Research Center from the National Institute of Child Health and Human Development Core Grant P30-HD03352. Madeline Harms was supported by T32-MH018931. We acknowledge the assistance of M. Daniela Cornejo, Joanna Swinarska, Alex Rokni, and Anna Bechner. We also appreciate the generous participation of the individuals who agreed to partake in this study.

References

Arnsten, F. T. (2009). Stress signalling pathways that impair prefrontal cortex structure and function. Nature Reviews Neuroscience, 10, 410422.Google Scholar
Belanoff, J. K., Gross, K., Yager, A., & Schatzberg, A. F. (2001). Corticosteroids and cognition. Journal of Psychiatric Research, 35, 127145.CrossRefGoogle ScholarPubMed
Bick, J., & Nelson, C. A. (2016). Early adverse experiences and the developing brain. Neuropsychopharmacology Reviews, 41, 177196.Google Scholar
Binder, E. B., Bradley, R. G., Liu, W., Epstein, M. P., Deveau, T. C., Mercer, K. B., … Ressler, K. J. (2008). Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. Journal of the American Medical Association, 299, 12911305.Google Scholar
Blakemore, S. J., & Choudhury, S. (2006). Development of the adolescent brain: Implications for executive function and social cognition. Journal of Child and Adolescent Pharmacology, 47, 296312.Google Scholar
Bogacz, R., Wagenmakers, E. J., Forstmann, B. U., & Niuwenhuis, S. (2009). The neural basis of the speed-accuracy tradeoff. Trends in Neurosciences, 33, 1016.Google Scholar
Bruce, J., Fisher, P. A., Graham, A. M., Moore, W. E., Peake, S. J., & Mannering, A. M. (2013). Patterns of brain activation in foster childern and nonmaltreated children during an inhibitory control task. Development and Psychopathology, 25, 931941.CrossRefGoogle Scholar
Bunge, S. A., Dudukovic, N. M., Thomason, M. E., Vaidya, C. J., & Gabrieli, J. D. E. (2002). Immature frontal lobe contributions to cognitive control in children: Evidence from fMRI. Neuron, 33, 301311.Google Scholar
Carrion, V. G., Garret, A., Menon, V., Weems, C. F., & Reiss, A. L. (2008). Posttraumatic stress symptoms and brain function during a response-inhibition task: An fMRI study in youth. Depression and Anxiety, 25, 514526.CrossRefGoogle ScholarPubMed
Cisler, J. M., James, G. A., Tripathi, S., & Mletzko, T. (2012). Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress. Psychological Medicine, 43, 507518.Google Scholar
Cowell, R. A., Cicchetti, D., Rogosch, F. A., & Toth, S. L. (2015). Maltreatment and its effect on neurocognitive functioning: Timing and chronicity matter. Development and Psychopathology, 27, 521533.Google Scholar
Cox, R. W. (1996). AFNI: Software for analysis and visualization of functional magnetic resonance neuroimages. Computers & Biomedical Research, 29, 162173.Google Scholar
Cox, R. W., Chen, G., Glen, D. R., Reynolds, R. C., & Taylor, P. A. (2017). fMRI clustering and false-positive rates. Proceedings of the National Academy of Sciences, 114, E3370E3371.CrossRefGoogle ScholarPubMed
Criaud, M., & Boulinguez, P. (2013). Have we been asking the right questions when assessing response inhibition in go/no-go tasks with fMRI? A meta-analysis and critical review. Neuroscience & Biobehavioral Reviews, 37, 1123.Google Scholar
de Berker, A. O., Tirole, M., Rutledge, R. B., Cross, G. F., Dolan, R. J., & Bestmann, S. (2016). Acute stress selectively impairs learning to act. Scientific Reports, 6, 29816. doi:10.1038/srep29816 Google Scholar
dePrince, A. P., Weinzierl, K. M., & Combs, M. D. (2009). Executive function performance and trauma exposure in a community sample of children. Child Abuse and Neglect, 33, 353361.Google Scholar
Durston, S., Thomas, K. M., Yang, Y., Ulug, A. M., Zimmerman, R. D., & Casey, B. J. (2002). A neural basis for the development of inhibitory control. Developmental Science, 5, F9F16.Google Scholar
Evans, G. W., Li, D., & Whipple, S. S. (2013). Cumulative risk and child development. Psychological Bulletin, 139, 13421396.Google Scholar
Gee, D. G., Gabard-Durnam, L. J., Flannery, J., Goff, B., Humphreys, K. L., Telzer, E. H., … Tottenham, N. (2013). Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation. Proceedings of the National Academy of Sciences, 110, 1563815643.Google Scholar
Gunnar, M. R. (2016). Early life stress: What is the human chapter of the mammalian story? Child Development Perspectives, 10, 178183.CrossRefGoogle Scholar
Hammen, C., Adrian, C., Gordon, D., Burge, D., Jaenicki, C., & Hiroto, D. (1987). Children of depressed mothers: Maternal strain and symptom predictors of dysfunction. Journal of Abnormal Psychology, 96, 190198.Google Scholar
Hanson, J. L., Bos, W., Roeber, B. J., Rudolph, K. D., Davidson, R. J., & Pollak, S. D. (2017). Early adversity and learning: Implications for typical and atypical behavioral development. Advance online publication. Journal of Child Psychology and Psychiatry.Google Scholar
Hanson, J. L., Chung, M. K., Avants, B. B., Shirtcliff, E. A., Gee, J. C., Davidson, J. R. T., & Pollak, S. D. (2010). Early stress is associated with alterations in the orbitofrontal cortex: A tensor-based morphometry investigation of brain structure and behavioral risk. Journal of Neuroscience, 30, 74667472.Google Scholar
Hanson, J. L., Nacewicz, B. M., Sutterer, M. J., Cayo, A. A., Schaefer, S. M., Rudolph, K. L., … Davidson, R. J. (2015). Behavioral problems after early life stress: Contributions of the hippocampus and amygdala. Biological Psychiatry, 77, 314323.Google Scholar
Harms, M. B., Shannon-Bowen, K., Hanson, J. L., & Pollak, S. D. (in press). Instrumental learning and cognitive flexibility processes are impaired in children exposed to early life stress. Developmental Science.Google Scholar
Harms, M. B., Zayas, V., Meltzoff, A. N., & Carlson, S. M. (2014). Stability of executive function and predictions to adaptive behavior from middle childhood to pre-adolescence. Frontiers in Psychology, 5, 331. doi:10.3389/fpsyg.2014.00331 Google Scholar
Hodel, A. S., Hunt, R. H., Cowell, R. A., van den Heuvel, S. E., Gunnar, M. E., & Thomas, K. M. (2015). Duration of early adversity and structural brain development in post-institutionalized adolescents. NeuroImage, 105, 112119.Google Scholar
Hoffmann, A., & Spengler, D. (2014). DNA memories of early social life. Journal of Neuroscience, 264, 6475.CrossRefGoogle ScholarPubMed
Jankowski, K. F., Bruce, J., Beauchamp, K. G., Roos, L. E., Moore, W. E., & Fisher, P. A. (2016). Preliminary evidence of the impact of early maltreatment and a preventive intervention on neural patterns of response inhibition in early adolescence. Developmental Science. Advance online publication. doi:10.1111/desc.12413 Google Scholar
Jovanovic, T., Ely, T., Fani, N., Glover, E. M., Gutman, D., Tone, E. B., … Kessler, R. J. (2013). Reduced neural activation during an inhibition task is associated with impaired fear inhibition in a traumatized civilian sample. Cortex, 49, 18841891.Google Scholar
Kaufman, J. N., Ross, T. J., Stein, E. A., & Garavan, H. (2003). Cingulate hypoactivity in cocaine users during a GO-NOGO task as revealed by functional magnetic resonance imaging. Journal of Neuroscience, 23, 78397843.Google Scholar
Kelly, P. A., Viding, E., Wallace, G. L., Schaer, M., De Brito, S. A., Robustelli, B., & McCrory, E. J. (2013). Cortical thickness, surface area, and gyrification abnormalities in children exposed to maltreatment: Neural markers of vulnerability? Biological Psychiatry, 74, 845852.Google Scholar
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, J. C., … Binder, E. B. (2013). Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neuroscience, 16, 3341.Google Scholar
MacKinnon, D. P., Lockwood, C. M., Hoffman, J. M., West, S. G., & Sheets, V. A (2002). Comparison of methods to test mediation and other intervening variable effects. Psychological Methods, 7, 83104.Google Scholar
McDermott, J. M., Westerlund, A., Zeanah, C. H., Nelson, C. A., & Fox, N. A. (2012). Early adversity and neural correlates of executive function: Implications for academic adjustment. Developmental Cognitive Neuroscience, 2, S59S66.Google Scholar
McEwen, B. S., & Sapolsky, R. M. (1995). Stress and cognitive function. Current Opinion in Neurobiology, 5, 205216.Google Scholar
Menon, V., Adleman, N. E., White, C. D., Glover, G. H., & Reiss, A. L. (2001). Error-related brain activation during a go/nogo response inhibition task. Human Brain Mapping, 12, 131143.3.0.CO;2-C>CrossRefGoogle ScholarPubMed
Mizoguchi, K., Ishige, A., Aburada, M., & Tabira, T. (2003). Chronic stress attenuates glucocorticoid negative feedback: Involvement of the prefrontal cortex and hippocampus. Neuroscience, 119, 887897.CrossRefGoogle ScholarPubMed
Mueller, S. C., Maheu, F. S., Dozier, M., Peloso, E., Mandell, D., Leibenluft, E., … Ernst, M. (2010). Early-life stress is associated with impairment in cognitive control in adolescence: An fMRI study. Neuropsychologia, 48, 30373044.Google Scholar
Nieuwenhuis, S., Ridderinkhof, K. R., Blom, J., Band, G. P., & Kok, A. (2001). Error-related brain potentials are differentially related to awareness of response errors: Evidence from an antisaccade task. Psychophysiology, 38, 752760.Google Scholar
Norman, R. E., Byambaa, M., De, R., Butchart, A., Scott, J., & Vos, T. (2012). The long-term health consequences of child physical abuse, emotional abuse, and neglect: A systematic review and meta-analysis. PLOS MED, 9, e1001349, doi:10.1371/journal.pmed.1001349 Google Scholar
Pechtel, P., & Pizzagalli, D. A. (2011). Effects of early life stress on cognitive and affective function: An integrated review of human literature. Psychopharmacology, 214, 5570.Google Scholar
Pollak, S. D. (2015). Multilevel developmental approaches to understanding the effects of child maltreatment: Recent advances and future challenges. Development and Psychopathology, 27(4, Pt. 2), 13871397.Google Scholar
Radley, J. J., Sisti, H. M., Hao, J., Rocher, A. B., McCall, T., Hof, P. R., … Morrison, J. H. (2004). Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Journal of Neuroscience, 125, 16.Google Scholar
Rahdar, A., & Galvan, A. (2014). The cognitive and neurobiological effects of daily stress in adolescents. NeuroImage, 15, 267273. doi:10.1016/j.neuroimage.2014.02.007 Google Scholar
Rubia, K., Smith, A. B., Taylor, E., & Brammer, M. (2007). Linear age-correlated functional development of right inferior fronto-striato-cerebella networks during response inhibition and anterior cingulate during error-related processes. Human Brain Mapping, 28, 11631177.Google Scholar
Rudolph, K. D., & Flynn, M. (2007). Childhood adversity and youth depression: Influence of gender and pubertal status. Development and Psychopathology, 19, 497521.Google Scholar
Rudolph, K. D., Hammen, C., Burge, D., Lingbeg, N., Herzberg, D., & Daley, S. E. (2000). Toward an interpersonal life-stress model of depression: The developmental context of stress generation. Development and Psychopathology, 12, 215234.Google Scholar
Russo, S. J., Murrough, J. W., Han, M. H., Charney, D. S., & Nestler, E. J. (2012). Neurobiology of resilience. Nature Neuroscience, 15, 14751484.Google Scholar
Scott, K. M., Smith, D. R., & Ellis, P. M. (2010). Prospectively ascertained child maltreatment and its association with DSM-IV mental disorders in young adults. Archives of General Psychiatry, 67, 712719.Google Scholar
Shonkoff, J. P., & Garner, A. S. (2011). The lifelong effects of early childhood adversity and toxic stress. Pediatrics, 129, e232e246. doi:10.1542/peds.2011-2663 CrossRefGoogle ScholarPubMed
Simmonds, D. J., Pekar, J. J., & Mostofsky, S. H. (2008). Meta-analysis of go/no-go tasks demonstrating that fMRI activation associated with response inhibition is task-dependent. Neuropsychologia, 46, 224232.Google Scholar
Steven, J. S., Ely, T. D., Sawamura, T., Guzman, D., Bradley, B., & Ressler, K. J. (2016). Childhood maltreatment predicts reduced inhibition-related activity in the rostral anterior cingulate in PTSD, but not trauma-exposed controls. Depression and Anxiety, 33, 614622. doi:10.1002/da.22506 CrossRefGoogle Scholar
Weller, J. A., & Fisher, P. A. (2012). Decision-making deficits among maltreated children. Child Maltreatment, 18, 184194.Google Scholar
White, M. G., Bogdan, R., Fisher, P. M., Munoz, K. E., Williamson, D. E., & Hariri, A. R. (2012). FKBP5 and emotional neglect interact to predict individual differences in amygdala reactivity. Genes, Brain, & Behavior, 11, 869979. doi:10.1111/j.1601-183X.2012.00837.x Google Scholar
Zannas, A. S., & Binder, E. B. (2013). Gene-environment interactions at the FKBP5 locus: Sensitive periods, mechanisms, and pleiotropism. Genes, Brain, & Behavior, 13, 2537.Google Scholar
Zannas, A. S., Wiechmann, T., Gassen, N. C., & Binder, E. B. (2016). Gene-stress-epigenetic regulation of FKBP5: Clinical and translational implications. Neuropsychopharmacology Reviews, 41, 261274.Google Scholar