Elsevier

NeuroImage

Volume 95, 15 July 2014, Pages 193-207
NeuroImage

The development of human amygdala functional connectivity at rest from 4 to 23 years: A cross-sectional study

https://doi.org/10.1016/j.neuroimage.2014.03.038Get rights and content

Highlights

  • Amygdala resting functional connectivity (FC) was assessed in 4- through 23-year olds.

  • Most FC with amygdala does not change during this period, resembling adult patterns.

  • FC with medial PFC, insula/STS, and PCC/hippocampus shows age-dependent changes.

  • Age-dependent FC transitions occur between childhood and adolescence (10–11 years).

  • Subnuclei analyses confirmed that most robust developmental change is with medial PFC.

Abstract

Functional connections (FC) between the amygdala and cortical and subcortical regions underlie a range of affective and cognitive processes. Despite the central role amygdala networks have in these functions, the normative developmental emergence of FC between the amygdala and the rest of the brain is still largely undefined. This study employed amygdala subregion maps and resting-state functional magnetic resonance imaging to characterize the typical development of human amygdala FC from age 4 to 23 years old (n = 58). Amygdala FC with subcortical and limbic regions was largely stable across this developmental period. However, three cortical regions exhibited age-dependent changes in FC: amygdala FC with the medial prefrontal cortex (mPFC) increased with age, amygdala FC with a region including the insula and superior temporal sulcus decreased with age, and amygdala FC with a region encompassing the parahippocampal gyrus and posterior cingulate also decreased with age. The transition from childhood to adolescence (around age 10 years) marked an important change-point in the nature of amygdala–cortical FC. We distinguished unique developmental patterns of coupling for three amygdala subregions and found particularly robust convergence of FC for all subregions with the mPFC. These findings suggest that there are extensive changes in amygdala–cortical functional connectivity that emerge between childhood and adolescence.

Introduction

Activity of the amygdala and the associated cortex underlies emotional attention, learning, and regulation (Adolphs and Spezio, 2006, Ochsner et al., 2012, Phillips et al., 2003). A robust human neuroimaging literature has shown that it is the functional connections between regions in these networks that underlie these affective and cognitive processes (Hariri et al., 2003, Kim et al., 2011a, Ochsner et al., 2012), and the strength of these functional connections has predicted emotional behaviors of healthy adults (Banks et al., 2007, Lee et al., 2012). Furthermore, atypical functional connectivity patterns within these networks have been implicated in disrupted affective and cognitive processes in a range of clinical populations, including those with anxiety, depression, schizophrenia, and bipolar disorder (Anand et al., 2005, Berking and Wupperman, 2012, Cisler and Olatunji, 2012, Das et al., 2007, Henry et al., 2008, Wang et al., 2009). Intrinsic, “resting” activity is critical for maintaining the integrity of functional connections, accounting for the vast majority of the brain's energy expenditure, so resting-state functional magnetic resonance imaging (fMRI) indexing these connections is a powerful approach for understanding composition and stability of these functional networks (Raichle, 2010, Tomasi et al., 2013).

Importantly, studies assessing amygdala–cortical functional connectivity through both resting-state and task analyses have focused on mature networks in adults, while the development of these functional connections is yet largely uncharacterized. Dramatic changes occur across childhood and adolescence in emotional behaviors that have been associated with amygdala-mediated cortical functional connections (e.g., emotion processing tasks: Gee et al., 2013, Hare et al., 2008, Perlman and Pelphrey, 2011; emotion reappraisal: McRae et al., 2012). Notably, the human amygdala's early maturation and functionality in childhood (Gee et al., 2013, Gilmore et al., 2012, Swartz et al., 2014, Thomas et al., 2001, Ulfig et al., 2003), along with the late maturation and functional development of cortical regions that can extend into adulthood together delineate a vast age-range during which amygdala–cortical functional connections may develop (Bunge et al., 2002, Casey et al., 1997, Casey et al., 2000, Giedd et al., 1996, Gogtay et al., 2004, Killgore and Yurgelun-Todd, 2004, Sowell et al., 2007). Qin et al. (2012) have recently noted weaker amygdala–cortical resting-state connectivity strengths in children (ages 7–9) compared to adults (ages 19–22). This paper was important because it showed that resting-state amygdala–cortical connectivity was different between children and adults. In the current study, we aimed to extend these findings by characterizing the timing and extent of changes in functional connectivity during development within the framework of a cross-sectional design. Characterizing the changes between early childhood and adulthood in these cortical and subcortical networks' construction can begin to inform how and when functional connections with the amygdala appear, delineate developmental transitions in these networks' construction, and identify periods of plasticity when these connections are sensitive to environmental influences (Sporns and Zwi, 2004).

We therefore assessed amygdala–cortical and subcortical functional connectivity development cross-sectionally from age 4–23 years using resting-state fMRI, which is ideal for participants spanning such a wide age-range (Pizoli et al., 2011, Uddin et al., 2010, Van Dijk et al., 2010). Specifically, we distinguished between age-controlled and age-dependent connectivity patterns with the amygdala. We anticipated that some regions would show mature connectivity with the amygdala by childhood, and sought to identify those regions that showed developmental change as well as quantify the timing, nature, and duration of these changes.

Secondly, while human studies have largely assessed connectivity with the amygdala as a homogenous structure, it is a complex of structurally and functionally distinct nuclei (Amaral et al., 1992, Amunts et al., 2005, LeDoux, 2003, Price, 2003). Initial studies using anatomical maps demonstrate the utility in differentiating these subregions in humans, finding both distinct activations and functional networks across subregions (Ball et al., 2007, Roy et al., 2009). Weaker segregation in functional connectivity to several target networks has been noted across amygdala subregions in a sample of children compared with adults (Qin et al., 2012), but the age-related changes in functional connectivity specific to each subregion and shared across subregions remain unknown. We characterized both the connectivity patterns differentiating each subregion in age-controlled and age-dependent analyses and assessed how these patterns converged across development to comprehensively examine the construction of amygdala networks from early childhood through adulthood.

Section snippets

Participants

Fifty-eight children, adolescents, and adults ages 4 to 23 years (mean age (S.D.) = 13.4 (4.8); 29 females, 29 males) contributed usable resting-state MRI data for this study (for participant age distribution, see Fig. 1). Handedness assessments using the Physical and Neurological Examination for Subtle Signs (PANESS) were available for 55 participants, such that 51 participants were right-handed, 3 were left-handed, and 1 reported using both hands for daily tasks (neither the left-handed nor the

Age-controlled functional coupling with the amygdala

We used ANCOVA to identify functional coupling with the amygdala (coupling parameters that were significantly different from zero), controlling for age and subject motion effects (whole-brain corrected p < 0.05). This analysis revealed that there was functional connectivity between the amygdala and the ventral/limbic and dorsal/posterior regions that was constant across this age-range. Specifically, the amygdala showed positive coupling with ventral and limbic regions including the bilateral

Discussion

We used resting-state fMRI across an extensive developmental period from age 4 to 23 years old in a cross-sectional design to map the whole-brain patterns of functional coupling with the bilateral amygdala that were stable across this period as well as to characterize the trajectories and patterns of age-related changes in coupling. Resting-state fMRI has been shown to index the stability and integrity of connections in functional networks, possibly reflecting the development of synaptic

Funding

This work was supported by the National Institute of Mental Health (R01MH091864 to N.T.) and the National Science Foundation (DGE-1144087 to L.J.G-D).

Conflict of interest

The authors declare no competing financial interests.

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