Functional Connectivity within the Primate Extended Amygdala Is Heritable and Associated with Early-Life Anxious Temperament

Children with an extremely inhibited, anxious temperament (AT) are at increased risk for anxiety disorders and depression. Using a rhesus monkey model of early-life AT, we previously demonstrated that metabolism in the central extended amygdala (EAc), including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST), is associated with trait-like variation in AT. Here, we use fMRI to examine relationships between Ce–BST functional connectivity and AT in a large multigenerational family pedigree of rhesus monkeys (n = 170 females and 208 males). Results demonstrate that Ce–BST functional connectivity is heritable, accounts for a significant but modest portion of the variance in AT, and is coheritable with AT. Interestingly, Ce–BST functional connectivity and AT-related BST metabolism were not correlated and accounted for non-overlapping variance in AT. Exploratory analyses suggest that Ce–BST functional connectivity is associated with metabolism in the hypothalamus and periaqueductal gray. Together, these results suggest the importance of coordinated function within the EAc for determining individual differences in AT and metabolism in brain regions associated with its behavioral and neuroendocrine components. SIGNIFICANCE STATEMENT Anxiety disorders directly impact the lives of nearly one in five people, accounting for substantial worldwide suffering and disability. Here, we use a nonhuman primate model of anxious temperament (AT) to understand the neurobiology underlying the early-life risk to develop anxiety disorders. Leveraging the same kinds of neuroimaging measures routinely used in human studies, we demonstrate that coordinated activation between the central nucleus of the amygdala and the bed nucleus of the stria terminalis is correlated with, and coinherited with, early-life AT. Understanding how these central extended amygdala regions work together to produce extreme anxiety provides a neural target for early-life interventions with the promise of preventing lifelong disability in at-risk children.

[1]  Do P. M. Tromp,et al.  Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit , 2016, Biological Psychiatry.

[2]  M. Davis,et al.  Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses , 2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[3]  F. Waal,et al.  "Coo" Vocalizations in Stumptailed Macaques: a Controlled Functional Analysis , 1991 .

[4]  S. Shelton,et al.  Individual differences in freezing and cortisol in infant and mother rhesus monkeys. , 1998, Behavioral neuroscience.

[5]  J. Clauss,et al.  The Human BNST: Functional Role in Anxiety and Addiction , 2016, Neuropsychopharmacology.

[6]  Michael C Neale,et al.  The structure of genetic and environmental risk factors for anxiety disorders in men and women. , 2005, Archives of general psychiatry.

[7]  Mert R. Sabuncu,et al.  Heritability analysis with repeat measurements and its application to resting-state functional connectivity , 2017, Proceedings of the National Academy of Sciences.

[8]  J. Heckman,et al.  A gradient of childhood self-control predicts health, wealth, and public safety , 2011, Proceedings of the National Academy of Sciences.

[9]  S. Shelton,et al.  Ontogeny and stability of separation and threat‐induced defensive behaviors in rhesus monkeys during the first year of life , 1998, American journal of primatology.

[10]  P. Fox,et al.  Genetic control over the resting brain , 2010, Proceedings of the National Academy of Sciences.

[11]  Russell T. Shinohara,et al.  Elevated Amygdala Perfusion Mediates Developmental Sex Differences in Trait Anxiety , 2016, Biological Psychiatry.

[12]  Eduardo E. Benarroch,et al.  Periaqueductal gray , 2012, Neurology.

[13]  M. Rietschel,et al.  Neuropsychosocial profiles of current and future adolescent alcohol misusers , 2014, Nature.

[14]  H. Pape,et al.  Cannabinoid CB1 receptors in distinct circuits of the extended amygdala determine fear responsiveness to unpredictable threat , 2017, Molecular Psychiatry.

[15]  Do P. M. Tromp,et al.  Dispositional negativity: An integrative psychological and neurobiological perspective. , 2016, Psychological bulletin.

[16]  J. Fudge,et al.  Resting state connectivity of the bed nucleus of the stria terminalis at ultra‐high field , 2015, Human brain mapping.

[17]  Richard J. Davidson,et al.  Intergenerational neural mediators of early-life anxious temperament , 2015, Proceedings of the National Academy of Sciences.

[18]  Monique Ernst,et al.  Intrinsic functional connectivity of the central nucleus of the amygdala and bed nucleus of the stria terminalis , 2017, NeuroImage.

[19]  Todd B. Parrish,et al.  Impact of signal‐to‐noise on functional MRI , 2000 .

[20]  Richard J. Davidson,et al.  Serotonin transporter binding and genotype in the nonhuman primate brain using [C-11]DASB PET , 2009, NeuroImage.

[21]  Do P. M. Tromp,et al.  Extending the amygdala in theories of threat processing , 2015, Trends in Neurosciences.

[22]  A. Shackman,et al.  The central extended amygdala in fear and anxiety: Closing the gap between mechanistic and neuroimaging research , 2017, Neuroscience Letters.

[23]  J. Kagan,et al.  Biological bases of childhood shyness. , 1988, Science.

[24]  L. Heimer,et al.  New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: The striatopallidal, amygdaloid, and corticopetal components of substantia innominata , 1988, Neuroscience.

[25]  Valérie Ferreira,et al.  Current use of benzodiazepines in anxiety disorders , 2009, Current opinion in psychiatry.

[26]  Richard J. Davidson,et al.  Evidence for coordinated functional activity within the extended amygdala of non-human and human primates , 2012, NeuroImage.

[27]  S. Shelton,et al.  The Role of the Central Nucleus of the Amygdala in Mediating Fear and Anxiety in the Primate , 2004, The Journal of Neuroscience.

[28]  P. Cuijpers,et al.  How effective are cognitive behavior therapies for major depression and anxiety disorders? A meta‐analytic update of the evidence , 2016, World psychiatry : official journal of the World Psychiatric Association.

[29]  D. Paré,et al.  Functional Heterogeneity in the Bed Nucleus of the Stria Terminalis , 2016, The Journal of Neuroscience.

[30]  Richard J. Davidson,et al.  Amygdalar and hippocampal substrates of anxious temperament differ in their heritability , 2010, Nature.

[31]  A. Bystritsky.  Treatment-resistant anxiety disorders , 2006, Molecular Psychiatry.

[32]  James H. Marshel,et al.  Diverging neural pathways assemble a behavioural state from separable features in anxiety , 2013, Nature.

[33]  A. Shackman,et al.  Contributions of the Central Extended Amygdala to Fear and Anxiety , 2016, The Journal of Neuroscience.

[34]  L. Orbeli.  [Physiology and psychology]. , 1946, Fiziologicheskii zhurnal SSSR imeni I. M. Sechenova.

[35]  Thomas Straube,et al.  Phasic and sustained brain responses in the amygdala and the bed nucleus of the stria terminalis during threat anticipation , 2016, Human brain mapping.

[36]  J. Kagan,et al.  Temperament, emotion, and cognition at fourteen months: the MacArthur Longitudinal Twin Study. , 1992, Child development.

[37]  Victoria Chapman,et al.  The role of the central nucleus of the amygdala in nociception and aversion , 2003, Neuroreport.

[38]  L. Heimer,et al.  Chapter II – The human basal forebrain. Part II , 1999 .

[39]  R. Muñoz.  Anxiety disorders. , 1986, New directions for mental health services.

[40]  Guy B. Williams,et al.  The impact of skull-stripping and radio-frequency bias correction on grey-matter segmentation for voxel-based morphometry , 2008, NeuroImage.

[41]  Thomas E. Nichols,et al.  The heritability of multi-modal connectivity in human brain activity , 2017, eLife.

[42]  D. Paré,et al.  Timing of impulses from the central amygdala and bed nucleus of the stria terminalis to the brain stem. , 2008, Journal of neurophysiology.

[43]  O Sporns,et al.  Predicting human resting-state functional connectivity from structural connectivity , 2009, Proceedings of the National Academy of Sciences.

[44]  L. Keele,et al.  A General Approach to Causal Mediation Analysis , 2010, Psychological methods.

[45]  N. Kalin,et al.  Connectivity between the central nucleus of the amygdala and the bed nucleus of the stria terminalis in the non-human primate: neuronal tract tracing and developmental neuroimaging studies , 2016, Brain Structure and Function.

[46]  Karl Deisseroth,et al.  Midbrain circuits for defensive behaviour , 2016, Nature.

[47]  N. Kalin,et al.  Nonhuman Primate Models to Study Anxiety, Emotion Regulation, and Psychopathology , 2003, Annals of the New York Academy of Sciences.

[48]  K. E. Nichols,et al.  Behavioral inhibition: linking biology and behavior within a developmental framework. , 2005, Annual review of psychology.

[49]  Ned H Kalin,et al.  Calling for help is independently modulated by brain systems underlying goal-directed behavior and threat perception. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Thomas E. Nichols,et al.  Scanning the horizon: towards transparent and reproducible neuroimaging research , 2016, Nature Reviews Neuroscience.

[51]  J. Clauss,et al.  Behavioral inhibition and risk for developing social anxiety disorder: a meta-analytic study. , 2012, Journal of the American Academy of Child and Adolescent Psychiatry.

[52]  Arno Klein,et al.  A reproducible evaluation of ANTs similarity metric performance in brain image registration , 2011, NeuroImage.

[53]  J. Rosenbaum,et al.  Behavioral inhibition , 2021, Depression and anxiety.

[54]  Ned H. Kalin,et al.  Mechanisms underlying the early risk to develop anxiety and depression: A translational approach , 2017, European Neuropsychopharmacology.

[55]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[56]  R. Beisteiner,et al.  The benefits of skull stripping in the normalization of clinical fMRI data☆ , 2013, NeuroImage: Clinical.

[57]  Richard J. Davidson,et al.  Subgenual Prefrontal Cortex Activity Predicts Individual Differences in Hypothalamic-Pituitary-Adrenal Activity Across Different Contexts , 2010, Biological Psychiatry.

[58]  Ned H Kalin,et al.  A translational neuroscience approach to understanding the development of social anxiety disorder and its pathophysiology. , 2014, The American journal of psychiatry.

[59]  Michael S. Beauchamp,et al.  A new method for improving functional-to-structural MRI alignment using local Pearson correlation , 2009, NeuroImage.

[60]  Martin J. Herrmann,et al.  Inter-individual differences in trait anxiety shape the functional connectivity between the bed nucleus of the stria terminalis and the amygdala during brief threat processing , 2018, NeuroImage.

[61]  G. McNally,et al.  The organization of defensive behavior elicited by optogenetic excitation of rat lateral or ventrolateral periaqueductal gray. , 2016, Behavioral neuroscience.

[62]  Georgina James,et al.  Cognitive behavioural therapy for anxiety disorders in children and adolescents. , 2015, The Cochrane database of systematic reviews.

[63]  R. Plomin,et al.  A twin study of anxiety-related behaviours in pre-school children. , 2003, Journal of child psychology and psychiatry, and allied disciplines.

[64]  A. Toga,et al.  The Rhesus Monkey Brain in Stereotaxic Coordinates , 1999 .

[65]  L. Almasy,et al.  Bivariate quantitative trait linkage analysis: Pleiotropy versus co‐incident linkages , 1997, Genetic epidemiology.

[66]  L. Heimer,et al.  The limbic lobe and its output channels: Implications for emotional functions and adaptive behavior , 2006, Neuroscience & Biobehavioral Reviews.

[67]  O. Bar‐Yosef,et al.  Modern humans in the Levant. , 1993, Scientific American.

[68]  R W Cox,et al.  AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. , 1996, Computers and biomedical research, an international journal.

[69]  A. Holmes,et al.  The Myth of Optimality in Clinical Neuroscience , 2018, Trends in Cognitive Sciences.

[70]  G H Glover,et al.  Image‐based method for retrospective correction of physiological motion effects in fMRI: RETROICOR , 2000, Magnetic resonance in medicine.

[71]  O. Sporns,et al.  Functional connectivity between anatomically unconnected areas is shaped by collective network-level effects in the macaque cortex. , 2012, Cerebral cortex.

[72]  Brian B. Avants,et al.  The optimal template effect in hippocampus studies of diseased populations , 2010, NeuroImage.

[73]  S. Shelton,et al.  Neural mechanisms underlying heterogeneity in the presentation of anxious temperament , 2013, Proceedings of the National Academy of Sciences.

[74]  Brendon M. Nacewicz,et al.  Intrinsic functional connectivity of the central extended amygdala , 2017, bioRxiv.

[75]  Richard J. Davidson,et al.  Brain Regions Associated with the Expression and Contextual Regulation of Anxiety in Primates , 2005, Biological Psychiatry.

[76]  Do P. M. Tromp,et al.  The Neurobiology of Dispositional Negativity and Attentional Biases to Threat: Implications for Understanding Anxiety Disorders in Adults and Youth , 2016, Journal of experimental psychopathology.

[77]  Kagan,et al.  The physiology and psychology of behavioral inhibition in children. , 1987, Child development.

[78]  S. Shelton,et al.  Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology , 2017, Molecular Psychiatry.

[79]  E. Lauterbach.  The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction , 1993 .

[80]  S. Shelton,et al.  Defensive behaviors in infant rhesus monkeys: environmental cues and neurochemical regulation. , 1989, Science.

[81]  B. F. Jeronimus,et al.  Neuroticism's prospective association with mental disorders halves after adjustment for baseline symptoms and psychiatric history, but the adjusted association hardly decays with time: a meta-analysis on 59 longitudinal/prospective studies with 443 313 participants , 2016, Psychological Medicine.

[82]  N. Kalin,et al.  The neurobiology of fear. , 1993, Scientific American.

[83]  Julie L. Fudge,et al.  Distribution of Serotonin Transporter Labeled Fibers in Amygdaloid Subregions: Implications for Mood Disorders , 2006, Biological Psychiatry.

[84]  M. Herrmann,et al.  Activity alterations in the bed nucleus of the stria terminalis and amygdala during threat anticipation in generalized anxiety disorder , 2017, Social cognitive and affective neuroscience.

[85]  Felix D. Schönbrodt,et al.  At what sample size do correlations stabilize , 2013 .

[86]  Bennett A. Landman,et al.  Statistical parametric mapping of brain morphology: Sensitivity is dramatically increased by using brain-extracted images as inputs , 2006, NeuroImage.

[87]  David Borsook,et al.  A role for fMRI in optimizing CNS drug development , 2006, Nature Reviews Drug Discovery.

[88]  Fenna M. Krienen,et al.  Opportunities and limitations of intrinsic functional connectivity MRI , 2013, Nature Neuroscience.

[89]  Karl Deisseroth,et al.  Integration of optogenetics with complementary methodologies in systems neuroscience , 2017, Nature Reviews Neuroscience.

[90]  Daniel H. Geschwind,et al.  Genetics and genomics of psychiatric disease , 2015, Science.

[91]  Hang Joon Jo,et al.  Mapping sources of correlation in resting state FMRI, with artifact detection and removal , 2010, NeuroImage.

[92]  R. N. Goble,et al.  Performance evaluation of the microPET P4: a PET system dedicated to animal imaging. , 2001, Physics in medicine and biology.

[93]  Ahmad R. Hariri,et al.  A Neural Biomarker of Psychological Vulnerability to Future Life Stress , 2015, Neuron.

[94]  M M Mesulam,et al.  Impact of signal-to-noise on functional MRI of the human amygdala , 2001, Neuroreport.

[95]  Luke J. Chang,et al.  Building better biomarkers: brain models in translational neuroimaging , 2017, Nature Neuroscience.

[96]  David G. Amaral,et al.  Neuroanatomy of the primate amygdala. , 2009 .

[97]  N. Logothetis.  What we can do and what we cannot do with fMRI , 2008, Nature.

[98]  Michael Davis,et al.  Double Dissociation between the Involvement of the Bed Nucleus of the Stria Terminalis and the Central Nucleus of the Amygdala in Startle Increases Produced by Conditioned versus Unconditioned Fear , 1997, The Journal of Neuroscience.

[99]  N. Canteras,et al.  The periaqueductal gray and primal emotional processing critical to influence complex defensive responses, fear learning and reward seeking , 2017, Neuroscience & Biobehavioral Reviews.

[100]  J. Kagan,et al.  Galen’s Prophecy , 2018 .

[101]  S. Shelton,et al.  Serotonin Transporter Availability in the Amygdala and Bed Nucleus of the Stria Terminalis Predicts Anxious Temperament and Brain Glucose Metabolic Activity , 2009, The Journal of Neuroscience.

[102]  P. van Eerdewegh,et al.  Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. I. Likelihood formulation and simulation results. , 1999, American journal of human genetics.

[103]  J. Simon Wiegert,et al.  Silencing Neurons: Tools, Applications, and Experimental Constraints , 2017, Neuron.

[104]  C. Grillon,et al.  Extended amygdala connectivity changes during sustained shock anticipation , 2018, Translational Psychiatry.

[105]  Kosuke Imai,et al.  mediation: R Package for Causal Mediation Analysis , 2014 .

[106]  Edward T. Bullmore,et al.  The future of functional MRI in clinical medicine , 2012, NeuroImage.

[107]  Richard J. Davidson,et al.  Trait-Like Brain Activity during Adolescence Predicts Anxious Temperament in Primates , 2008, PloS one.

[108]  Alexander J. Shackman,et al.  Getting Serious about Variation: Lessons for Clinical Neuroscience (A Commentary on ‘The Myth of Optimality in Clinical Neuroscience’) , 2018, Trends in Cognitive Sciences.

[109]  J. Kagan,et al.  Temperament, emotion, and cognition at fourteen months: the MacArthur Longitudinal Twin Study. , 1992, Child development.

[110]  J. Kagan,et al.  Genetic etiology of behavioral inhibition among 2-year-old children , 1994 .