# Puberty-related development of fronto-amygdala circuitry in anxious youth: A multimodal neuroimaging study with ultra-high resolution MRI scanner (7T)

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $766,641

## Abstract

Summary
Anxiety disorders, which onset during childhood or adolescence, often persist into adulthood, and increase the
risk of depression and suicide. Early adolescence, with the onset of puberty, is an important period for the
development and/or exacerbation of anxiety symptoms – i.e., Generalized Anxiety Disorder (GAD) and Social
Anxiety Disorder (SAD) – with higher levels of symptoms in girls than boys. During this time, fronto-amygdala
circuitry, which supports emotion regulation, undergoes important maturational changes. Although alterations in
this circuitry has been reported in anxiety disorders, the neurodevelopmental mechanisms underlying the sex
differences in levels of anxiety symptoms remain poorly understood. Compared to non-anxious youth, anxious
youth exhibit greater amygdala activation and reduced fronto-amygdala functional connectivity when processing
threat-related stimuli. Such reduced top–down modulation of amygdala activity to threat has been linked in
anxious adults to elevated concentrations in γ-aminobutyric acid (GABA) and glutamate in the ventromedial
prefrontal cortex (vmPFC) and amygdala, respectively. It has also been linked, including in anxious youth, to
reduced integrity of white matter tracts connecting vmPFC and amygdala (i.e., uncinate fasciculus and cingulum).
While vmPFC inhibition of amygdala activity increases with age, we and others have shown in healthy and at-
risk youth that increases in pubertal hormones, particularly testosterone, are associated with reduced vmPFC-
amygdala functional connectivity to threat. We will test the model that increases in pubertal hormones during
early adolescence will exacerbate alterations in fronto-amygdala circuitry in anxious youth and contribute to
greater threat reactivity and increases in anxiety symptoms, especially in girls. We test this hypothesis in a
sample of medication-free 140 adolescents (50% female), varying in levels of anxiety, with 2/3 oversampled for
clinical levels of GAD and SAD symptoms. We will repeatedly assess participants at five timepoints. At baseline
and approximately 2 years later, we will assess anxiety (clinical interviews, questionnaires), pubertal status
(Tanner, self-report), pubertal hormones (DHEA, testosterone, and estradiol), threat reactivity in a real-world
context with physiological and subjective measures of threat reactivity, and neural indices of vmPFC-amygdala
circuitry (fMRI during threat processing and at rest, white matter connectivity, and magnetic resonance
spectroscopy (MRS) measures of GABA and glutamate). Change in symptoms will be assessed bi-annually via
online questionnaires over 2 years post baseline visit. We use an ultra high-field MRI at 7 Tesla, which will yield
unprecedented characterization of vmPFC-amygdala neurodevelopment in anxious youth. We will also explore
the effects of pubertal hormones, anxiety, and threat reactivity on whole brain functional networks and examine
how each of the neural indices relate...

## Key facts

- **NIH application ID:** 10276587
- **Project number:** 1R01MH126979-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Cecile D. Ladouceur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $766,641
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276587

## Citation

> US National Institutes of Health, RePORTER application 10276587, Puberty-related development of fronto-amygdala circuitry in anxious youth: A multimodal neuroimaging study with ultra-high resolution MRI scanner (7T) (1R01MH126979-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10276587. Licensed CC0.

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