The NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty: Protocol and rationale for methods and measures

Abstract

Delineating the relationship between human neurodevelopment and the maturation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty is critical for investigating the increase in vulnerability to neuropsychiatric disorders that is well documented during this period. Preclinical research demonstrates a clear association between gonadal production of sex steroids and neurodevelopment; however, identifying similar associations in humans has been complicated by confounding variables (such as age) and the coactivation of two additional endocrine systems (the adrenal androgenic system and the somatotropic growth axis) and requires further elucidation. In this paper, we present the design of, and preliminary observations from, the ongoing NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty. The aim of this study is to directly examine how the increase in sex steroid hormone production following activation of the HPG-axis (i.e., gonadarche) impacts neurodevelopment, and, additionally, to determine how gonadal development and maturation is associated with longitudinal changes in brain structure and function in boys and girls. To disentangle the effects of sex steroids from those of age and other endocrine events on brain development, our study design includes 1) selection criteria that establish a well-characterized baseline cohort of healthy 8-year-old children prior to the onset of puberty (e.g., prior to puberty-related sex steroid hormone production); 2) temporally dense longitudinal, repeated-measures sampling of typically developing children at 8-10 month intervals over a 10-year period between the ages of eight and 18; 3) contemporaneous collection of endocrine and other measures of gonadal, adrenal, and growth axis function at each timepoint; and 4) collection of multimodal neuroimaging measures at these same timepoints, including brain structure (gray and white matter volume, cortical thickness and area, white matter integrity, myelination) and function (reward processing, emotional processing, inhibition/impulsivity, working memory, resting-state network connectivity, regional cerebral blood flow). This report of our ongoing longitudinal study 1) provides a comprehensive review of the endocrine events of puberty; 2) details our overall study design; 3) presents our selection criteria for study entry (e.g., well-characterized prepubertal baseline) along with the endocrinological considerations and guiding principles that underlie these criteria; 4) describes our longitudinal outcome measures and how they specifically relate to investigating the effects of gonadal development on brain development; and 5) documents patterns of fMRI activation and resting-state networks from an early, representative subsample of our cohort of prepubertal 8-year-old children.

Trial registration: ClinicalTrials.gov NCT01434368.

Keywords: Longitudinal design; Multimodal neuroimaging; Neurodevelopment; Neuroendocrinology; Puberty.

Copyright © 2021. Published by Elsevier Inc.

Figures

Figure 1.

Resting-state ICA Analysis. A total of thirteen independent components were identified as having high spatial overlap with one of the seven canonical networks identified in Yeo et al. (2011). For more information see supplemental methods.

Figure 2.

Stop Signal Task. Task consists of two trial types, (A) go trials and (B) stop trials. During both trial types, participants are presented with an image of a green traffic light superimposed with either a left or a right arrow and are asked to identify the direction of the arrow using a button box. In stop trials a red stop light is presented following the presentation of the arrow, indicating that the participant should not complete the button press. For more information see supplemental methods. Representative activation t-maps from the Successful Stop – Go contrast show robust task activation (p<.01 fdr-corrected in the dorsolateral prefrontal cortex ventrolateral middle frontal gyrus fusiform pre-supplemental motor area anterior cingulate and insula.>

Figure 3.

Reward Task. Task includes monetary reward trials in two levels of difficulty associated with anticipatory cues (i.e., screen background) including a (A) high probability green background or (B) low probability red background of reward, and (C) control trials where no monetary gain was possible (gray background) and participants could ‘win’ pieces of paper. High probability trials have a 67% chance of being easy (longer response time), low probability trials have a 67% chance of being difficult (shorter response time), while control trials have a 50:50 distribution of required response times. For more details see supplemental methods and Kohli et al. (2018). Representative activation t-maps from the Gain – Loss contrast (high and low probability hits -misses) show robust task activation (p<.01, FDR-corrected) in the ventral striatum (VS), middle frontal gyrus (MFG), and the lateral occipital cortex (lOC).

Figure 4.

Working Memory Task. The N-back task includes the presentation of one of five blocks including (A) a letter (verbal memory) and (B) a location (spatial memory) condition of either low (1-back) or high (2-back) memory load, as well as a sensorimotor control condition (0-back). Participants are asked to identify by button press whether the current stimulus category (letter or location) is the same as one they saw ‘N’ steps earlier (e.g., letter 2-back, same letter as 2 steps back). For the control condition, subjects are asked to respond with a button press when they see a zero appear on the screen. For more information see supplemental methods. Representative activation t-maps from the Location 1-back – 0-back contrast show robust task activation (p<.01 fdr-corrected in canonical working memory regions including the dorsolateral prefrontal cortex anterior cingulate inferior parietal lobule and lateral posterior>

Figure 5.

Emotional Faces Task. (A) Participants are presented with one of five blocks of images including faces or scenes of either high (aversive) or low (non-aversive) negative emotional valence as well as sensorimotor control (scrambled) images. Aversive face blocks include sad, angry, disgusted, and fearful faces while non-aversive face blocks include happy and neutral faces. (B) During each trial, participants view a target image at the top of the screen and are asked to select the matching image from two choices at the bottom of the screen with a left/right button press. For more information see supplemental methods. Representative activation t-maps from the Aversive Faces – Scramble contrast show robust task activation (p<.01 fdr-corrected in the amygdala and fusiform gyrus including face area negative parahippocampal was associated with positive activation scramble condition.>