The link between testosterone and amygdala–orbitofrontal cortex connectivity in adolescent alcohol use

Alcohol consumption is one of the most problematic and widespread forms of risk taking in adolescence. It has been hypothesized that sex hormones such as testosterone play an important role in risk taking by influencing the development of brain networks involved in emotion and motivation, particularly the amygdala and its functional connections. Connectivity between the amygdala and the orbitofrontal cortex (OFC) may be specifically related to alcohol use, given the association of this tract with top-down control over behavioral approach tendencies. In line with this, prior studies in adults indicate a link between alcohol use and functional connectivity between the amygdala and the orbitofrontal cortex (OFC), as well as between testosterone and amygdala-OFC connectivity. We consolidated these research lines by investigating the association between alcohol use, testosterone and resting state functional brain connectivity within one large-scale adolescent sample (n=173, aged 12-25 years). Mediation analyses demonstrated an indirect effect of testosterone levels on alcohol use through amygdala-OFC intrinsic functional connectivity, but only in boys. That is, increased testosterone in boys was associated with reduced amygdala-OFC connectivity, which in turn was associated with increased alcohol intake. This study is the first to demonstrate the interplay between adolescent alcohol use, sex hormones and brain mechanisms, thus taking an important step to increase our understanding of the mechanisms behind this form of adolescent risk-taking.

[1]  Erno J. Hermans,et al.  Exogenous Testosterone Enhances Responsiveness to Social Threat in the Neural Circuitry of Social Aggression in Humans , 2008, Biological Psychiatry.

[2]  Bonnie J Nagel,et al.  The impact of sex, puberty, and hormones on white matter microstructure in adolescents. , 2012, Cerebral cortex.

[3]  W. Mcbride.  Central nucleus of the amygdala and the effects of alcohol and alcohol-drinking behavior in rodents , 2002, Pharmacology Biochemistry and Behavior.

[4]  Steven J. Stanton,et al.  Endogenous testosterone levels are associated with amygdala and ventromedial prefrontal cortex responses to anger faces in men but not women , 2009, Biological Psychology.

[5]  Eveline A. Crone,et al.  Delay Discounting and Frontostriatal Fiber Tracts: A Combined DTI and MTR Study on Impulsive Choices in Healthy Young Adults , 2012, Cerebral cortex.

[6]  Laura Kann,et al.  Reliability of the 1999 youth risk behavior survey questionnaire. , 2002, The Journal of adolescent health : official publication of the Society for Adolescent Medicine.

[7]  P. Shrout,et al.  Mediation in experimental and nonexperimental studies: new procedures and recommendations. , 2002, Psychological methods.

[8]  Stephen M. Smith,et al.  General multilevel linear modeling for group analysis in FMRI , 2003, NeuroImage.

[9]  T. Paus,et al.  Sexual dimorphism in the adolescent brain: Role of testosterone and androgen receptor in global and local volumes of grey and white matter , 2010, Hormones and Behavior.

[10]  Ivo D Dinov,et al.  Puberty influences medial temporal lobe and cortical gray matter maturation differently in boys than girls matched for sexual maturity. , 2011, Cerebral cortex.

[11]  Kristopher J Preacher,et al.  Mediation Analysis in Social Psychology: Current Practices and New Recommendations , 2011 .

[12]  Kristopher J Preacher,et al.  SPSS and SAS procedures for estimating indirect effects in simple mediation models , 2004, Behavior research methods, instruments, & computers : a journal of the Psychonomic Society, Inc.

[13]  Keith J. Worsley,et al.  Statistical analysis of activation images , 2001 .

[14]  X. Zuo,et al.  Test-retest reliabilities of resting-state FMRI measurements in human brain functional connectomics: A systems neuroscience perspective , 2014, Neuroscience & Biobehavioral Reviews.

[15]  M. Kringelbach.  The human orbitofrontal cortex: linking reward to hedonic experience , 2005, Nature Reviews Neuroscience.

[16]  Ewald Moser,et al.  Amygdala activity to fear and anger in healthy young males is associated with testosterone , 2009, Psychoneuroendocrinology.

[17]  R. Dahl,et al.  The Teenage Brain , 2013 .

[18]  Jerry L. Grenard,et al.  Interactions between implicit and explicit cognition and working memory capacity in the prediction of alcohol use in at-risk adolescents. , 2008, Drug and alcohol dependence.

[19]  E. Witt.  Puberty, hormones, and sex differences in alcohol abuse and dependence. , 2007, Neurotoxicology and teratology.

[20]  F. Filbey,et al.  Adolescent risk-taking and resting state functional connectivity , 2014, Psychiatry Research: Neuroimaging.

[21]  Peter A. Bos,et al.  Acute effects of steroid hormones and neuropeptides on human social–emotional behavior: A review of single administration studies , 2012, Frontiers in Neuroendocrinology.

[22]  D. Hommer,et al.  Why We Like to Drink: A Functional Magnetic Resonance Imaging Study of the Rewarding and Anxiolytic Effects of Alcohol , 2008, The Journal of Neuroscience.

[23]  Stephen M. Smith,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[24]  T F Nelson,et al.  Binge drinking and the American college student: what's five drinks? , 2001, Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors.

[25]  D. Fitzgerald,et al.  Alcohol attenuates amygdala–frontal connectivity during processing social signals in heavy social drinkers , 2013, Psychopharmacology.

[26]  P. Shrout,et al.  Mediation in experimental and nonexperimental studies: new procedures and recommendations. , 2002, Psychological methods.

[27]  Stephen M. Smith,et al.  A global optimisation method for robust affine registration of brain images , 2001, Medical Image Anal..

[28]  M. Fox,et al.  Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging , 2007, Nature Reviews Neuroscience.

[29]  D. Mackinnon,et al.  Equivalence of the Mediation, Confounding and Suppression Effect , 2000, Prevention Science.

[30]  Kaustubh Supekar,et al.  Dynamic Reconfiguration of Structural and Functional Connectivity Across Core Neurocognitive Brain Networks with Development , 2011, The Journal of Neuroscience.

[31]  Guillén Fernández,et al.  Testosterone reduces amygdala–orbitofrontal cortex coupling , 2010, Psychoneuroendocrinology.

[32]  Jerry L. Grenard,et al.  Comparison of indirect assessments of association as predictors of marijuana use among at-risk adolescents. , 2007, Experimental and clinical psychopharmacology.

[33]  K. Bucholz,et al.  Adolescent alcohol use is a risk factor for adult alcohol and drug dependence: evidence from a twin design , 2005, Psychological Medicine.

[34]  Michael Brady,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[35]  Mark W. Woolrich,et al.  Multilevel linear modelling for FMRI group analysis using Bayesian inference , 2004, NeuroImage.

[36]  Richard J. Davidson,et al.  Amygdala–prefrontal coupling underlies individual differences in emotion regulation , 2012, NeuroImage.

[37]  E. Crone,et al.  Understanding adolescence as a period of social–affective engagement and goal flexibility , 2012, Nature Reviews Neuroscience.

[38]  R. Dahl,et al.  Pubertal testosterone influences threat-related amygdala-orbitofrontal cortex coupling. , 2015, Social cognitive and affective neuroscience.

[39]  Eveline A. Crone,et al.  Pubertal maturation and sex steroids are related to alcohol use in adolescents , 2013, Hormones and Behavior.

[40]  Erno J. Hermans,et al.  The neural mechanisms by which testosterone acts on interpersonal trust , 2012, NeuroImage.

[41]  Claire Wang,et al.  The neurocognitive effects of alcohol on adolescents and college students. , 2005, Preventive medicine.

[42]  Mark W. Woolrich,et al.  Robust group analysis using outlier inference , 2008, NeuroImage.

[43]  Stephen M Smith,et al.  Fast robust automated brain extraction , 2002, Human brain mapping.

[44]  T. Bjarnason,et al.  The 2011 ESPAD report: substance use among students in 36 European countries. , 2012 .

[45]  A. Hayes.  Beyond Baron and Kenny: Statistical Mediation Analysis in the New Millennium , 2009 .

[46]  Kristopher J Preacher,et al.  Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models , 2008, Behavior research methods.

[47]  L. Sobell,et al.  Self-Report Issues in Alcohol Abuse: State of the Art and Future Directions , 1990 .

[48]  M. Raichle.  Two views of brain function , 2010, Trends in Cognitive Sciences.

[49]  Eveline A. Crone,et al.  Development of Risk Taking: Contributions from Adolescent Testosterone and the Orbito-frontal Cortex , 2013, Journal of Cognitive Neuroscience.

[50]  Ahmad R. Hariri,et al.  Salivary testosterone and a trinucleotide (CAG) length polymorphism in the androgen receptor gene predict amygdala reactivity in men , 2010, Psychoneuroendocrinology.

[51]  Joshua M. Smyth,et al.  The amygdala: An agent of change in adolescent neural networks , 2013, Hormones and Behavior.

[52]  I. Olson,et al.  Dissecting the uncinate fasciculus: disorders, controversies and a hypothesis. , 2013, Brain : a journal of neurology.

[53]  Kamryn T. Eddy,et al.  Amygdala-frontal connectivity during emotion regulation. , 2007, Social cognitive and affective neuroscience.

[54]  M. Biehl,et al.  The Influence of Pubertal Timing on Alcohol Use and Heavy Drinking Trajectories , 2007 .

[55]  D. Hommer,et al.  Subjective and Neural Responses to Intravenous Alcohol in Young Adults with Light and Heavy Drinking Patterns , 2012, Neuropsychopharmacology.

[56]  S. West,et al.  A comparison of methods to test mediation and other intervening variable effects. , 2002, Psychological methods.

[57]  E. Murray,et al.  The amygdala and reward , 2002, Nature Reviews Neuroscience.

[58]  Alan C. Evans,et al.  Testosterone-related cortical maturation across childhood and adolescence. , 2012, Cerebral cortex.

[59]  A. Damasio,et al.  Emotion, decision making and the orbitofrontal cortex. , 2000, Cerebral cortex.

[60]  E. Westling,et al.  Pubertal timing and substance use: the effects of gender, parental monitoring and deviant peers. , 2008, The Journal of adolescent health : official publication of the Society for Adolescent Medicine.

[61]  Ronald E. Dahl,et al.  Pubertal development and behavior: Hormonal activation of social and motivational tendencies , 2010, Brain and Cognition.

[62]  L. Vatten,et al.  Sexual maturation in early adolescence and alcohol drinking and cigarette smoking in late adolescence: a prospective study of 2,129 Norwegian girls and boys , 2005, European Journal of Pediatrics.

[63]  L. Swanson,et al.  Distribution of androgen and estrogen receptor mRNA‐containing cells in the rat brain: An in situ hybridization study , 1990, The Journal of comparative neurology.

[64]  L. Steinberg.  A Social Neuroscience Perspective on Adolescent Risk-Taking. , 2008, Developmental review : DR.

[65]  Walter Schneider,et al.  Identifying the brain's most globally connected regions , 2010, NeuroImage.

[66]  Michael Angstadt,et al.  Effects of alcohol on brain responses to social signals of threat in humans , 2011, NeuroImage.

[67]  C. Lebel,et al.  Longitudinal Development of Human Brain Wiring Continues from Childhood into Adulthood , 2011, The Journal of Neuroscience.

[68]  R. Dahl,et al.  Pubertal development: correspondence between hormonal and physical development. , 2009, Child development.

[69]  Todd A. Hare,et al.  The development of human amygdala functional connectivity at rest from 4 to 23years: A cross-sectional study , 2014, NeuroImage.

[70]  John G. Lynch,et al.  Reconsidering Baron and Kenny: Myths and Truths about Mediation Analysis , 2010 .

[71]  David C. Glahn,et al.  Reduced Amygdala Activation in Young Adults at High Risk of Alcoholism: Studies from the Oklahoma Family Health Patterns Project , 2007, Biological Psychiatry.