Background
Early childhood anxiety has been linked to an increased risk for developing mood and
anxiety disorders. Little, however, is known about its effect on the brain during
a period in early childhood when anxiety-related traits begin to be reliably identifiable.
Even less is known about the neurodevelopmental origins of individual differences
in childhood anxiety.
Methods
We combined structural and functional magnetic resonance imaging with neuropsychological
assessments of anxiety based on daily life experiences to investigate the effects
of anxiety on the brain in 76 young children. We then used machine learning algorithms
with balanced cross-validation to examine brain-based predictors of individual differences
in childhood anxiety.
Results
Even in children as young as ages 7 to 9, high childhood anxiety is associated with
enlarged amygdala volume and this enlargement is localized specifically to the basolateral
amygdala. High childhood anxiety is also associated with increased connectivity between
the amygdala and distributed brain systems involved in attention, emotion perception,
and regulation, and these effects are most prominent in basolateral amygdala. Critically,
machine learning algorithms revealed that levels of childhood anxiety could be reliably
predicted by amygdala morphometry and intrinsic functional connectivity, with the
left basolateral amygdala emerging as the strongest predictor.
Conclusions
Individual differences in anxiety can be reliably detected with high predictive value
in amygdala-centric emotion circuits at a surprisingly young age. Our study provides
important new insights into the neurodevelopmental origins of anxiety and has significant
implications for the development of predictive biomarkers to identify children at
risk for anxiety disorders.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Anxiety and anxiety disorders in children and adolescents: Developmental issues and implications for DSM-V.Psychiatr Clin North Am. 2009; 32: 483-524
- Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.Arch Gen Psychiatry. 2005; 62: 593-602
- Early life influences on life-long patterns of behavior and health.Ment Retard Dev Disabil Res Rev. 2003; 9: 149-154
- Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: Associations with first onset of DSM-IV disorders.Arch Gen Psychiatry. 2010; 67: 113-123
- Mechanisms linking early life stress to adult health outcomes.Proc Natl Acad Sci U S A. 2012; 107: 8507-8512
- Social influences on neuroplasticity: Stress and interventions to promote well-being.Nat Neurosci. 2012; 15: 689-695
- Effects of stress throughout the lifespan on the brain, behaviour and cognition.Nat Rev Neurosci. 2009; 10: 434-445
- Emotion circuits in the brain.Annu Rev Neurosci. 2000; 23: 155-184
- Emotion processing and the amygdala: From a ‘low road’ to ‘many roads’ of evaluating biological significance.Nat Rev Neurosci. 2010; 11: 773-783
- Amygdala automaticity in emotional processing.Ann N Y Acad Sci. 2003; 985: 348-355
- Chronic-stress induced modulation of different states of anxiety-like behavior in female rats.Neurosci Lett. 2005; 383: 278-283
- Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala.Neuroscience. 2006; 143: 387-393
- Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy.Proc Natl Acad Sci U S A. 2008; 105: 5573-5578
- Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder.Arch Gen Psychiatry. 2009; 66: 1361-1372
- Pilot multimodal twin imaging study of generalized anxiety disorder.Depress Anxiety. 2012; 29: 202-209
- Localized gray matter volume abnormalities in generalized anxiety disorder.Eur Arch Psychiatry Clin Neurosci. 2011; 261: 303-307
- Volumetric associations between uncinate fasciculus, amygdala, and trait anxiety.BMC Neurosci. 2012; 13: 4
- Individual differences in amygdala-medial prefrontal anatomy link negative affect, impaired social functioning, and polygenic depression risk.J Neurosci. 2012; 32: 18087-18100
- Attenuation of frontal asymmetry in pediatric posttraumatic stress disorder.Biol Psychiatry. 2001; 50: 943-951
- A pilot study of amygdala volumes in pediatric generalized anxiety disorder.Biol Psychiatry. 2000; 48: 51-57
- Selective reduction in amygdala volume in pediatric anxiety disorders: A voxel-based morphometry investigation.Biol Psychiatry. 2005; 57: 961-966
- Hippocampal and amygdala volumes in children and adults with childhood maltreatment-related posttraumatic stress disorder: A meta-analysis.Hippocampus. 2008; 18: 729-736
- The brain basis of emotion: A meta-analytic review.Behav Brain Sci. 2012; 35: 121-143
- The amygdala.Curr Biol. 2007; 17: R868-R874
- Functional connectivity of the human amygdala using resting state fMRI.Neuroimage. 2009; 45: 614-626
- Manual for the ASEBA School-Age Forms & Profiles.University of Vermont, Research Center for Children, Youth, & Families, Burlington, VT2001
- Immature integration and segregation of emotion-related brain circuitry in young children.Proc Natl Acad Sci U S A. 2012; 109: 7941-7946
- Large-scale brain networks and psychopathology: A unifying triple network model.Trends Cogn Sci. 2011; 15: 483-506
- Enhanced resting-state connectivity of amygdala in the immediate aftermath of acute psychological stress.Neuroimage. 2010; 53: 348-354
- Anxiety dissociates dorsal and ventral medial prefrontal cortex functional connectivity with the amygdala at rest.Cereb Cortex. 2011; 21: 1667-1673
- Developmental maturation of dynamic causal control signals in higher-order cognition: A neurocognitive network model.PLoS Comput Biol. 2012; 8: e1002374
- An fMRI-based neurologic signature of physical pain.N Engl J Med. 2013; 368: 1388-1397
- Spiral-in/out BOLD fMRI for increased SNR and reduced susceptibility artifacts.Magn Reson Med. 2001; 46: 515-522
- Controlling the familywise error rate in functional neuroimaging: A comparative review.Stat Methods Med Res. 2003; 12: 419-446
- Decoding developmental differences and individual variability in response inhibition through predictive analyses across individuals.Front Hum Neurosci. 2010; 4: 47
- A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data.Neuroimage. 2005; 25: 1325-1335
- Functional connectivity in the resting brain: A network analysis of the default mode hypothesis.Proc Natl Acad Sci U S A. 2003; 100: 253-258
- Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion.Neuroimage. 2012; 59: 2142-2154
- Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.Am J Psychiatry. 2007; 164: 1476-1488
- Individual differences in recovery from traumatic fear.Trends Neurosci. 2013; 36: 23-31
- Larger amygdala but no change in hippocampal volume in 10-year-old children exposed to maternal depressive symptomatology since birth.Proc Natl Acad Sci U S A. 2011; 108: 14324-14329
- Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala.Proc Natl Acad Sci U S A. 2005; 102: 9371-9376
- Stress, memory and the amygdala.Nat Rev Neurosci. 2009; 10: 423-433
- Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior.Neuroscience. 2004; 128: 667-673
- Neurocognitive mechanisms of anxiety: An integrative account.Trends Cogn Sci. 2007; 11: 307-316
- Functional neuroanatomy of anxiety: A neural circuit perspective.Curr Top Behav Neurosci. 2010; 2: 251-277
- Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces.Neuron. 2004; 44: 1043-1055
- Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans.Neuron. 2011; 69: 563-571
- Neural substrates of childhood anxiety disorders: A review of neuroimaging findings.Child Adolesc Psychiatr Clin N Am. 2012; 21: 501-525
- From specificity to sensitivity: How acute stress affects amygdala processing of biologically salient stimuli.Biol Psychiatry. 2009; 66: 649-655
- Stress-related noradrenergic activity prompts large-scale neural network reconfiguration.Science. 2011; 334: 1151-1153
- Understanding low reliability of memories for neutral information encoded under stress: Alterations in memory-related activation in the hippocampus and midbrain.J Neurosci. 2012; 32: 4032-4041
- Cognitive theory and therapy of anxiety and depression: Convergence with neurobiological findings.Trends Cogn Sci. 2010; 14: 418-424
- Attentional bias in emotional disorders.J Abnorm Psychol. 1986; 95: 15-20
- The reward circuit: Linking primate anatomy and human imaging.Neuropsychopharmacology. 2010; 35: 4-26
- The nucleus accumbens: A target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders.J Chem Neuroanat. 2003; 26: 293-299
- Dissociable intrinsic connectivity networks for salience processing and executive control.J Neurosci. 2007; 27: 2349-2356
- Resting-state functional and structural connectivity within an insula-amygdala route specifically index state and trait anxiety.Biol Psychiatry. 2013; 73: 85-92
- Intrinsic amygdala-cortical functional connectivity predicts social network size in humans.J Neurosci. 2012; 32: 14729-14741
- Diathesis-stress theories in the context of life stress research: Implications for the depressive disorders.Psychol Bull. 1991; 110: 406-425
- Effects of early stress on behavioral syndromes: An integrated adaptive perspective.Neurosci Biobehav Rev. 2011; 35: 1452-1465
- Psychobiological processes of stress and coping: Implications for resilience in children and adolescents--comments on the papers of Romeo & McEwen and Fisher et al.Ann N Y Acad Sci. 2006; 1094: 226-234
- Understanding adolescence as a period of social-affective engagement and goal flexibility.Nat Rev Neurosci. 2012; 13: 636-650
Article info
Publication history
Published online: November 25, 2013
Accepted:
October 3,
2013
Received in revised form:
September 4,
2013
Received:
May 23,
2013
Identification
Copyright
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
