Gaelle Eve Doucet

Cortical gradients have been shown to be an effective technique to study the functional organization of the brain by capturing patterns of functional similarities. Until now, most studies have focused on analyzing cortical gradients derived from resting‐state fMRI. With recent work highlighting the changes that functional brain networks undergo during various cognitive loads, there is a need to investigate whether cortical gradients are also sensitive to different cognitive demands, and to what degree. In this context, we collected a sample of 138 healthy individuals aged 12–25, each of whom completed a resting‐state fMRI scan as well as three task fMRI scans (social prospection, spatial working memory, and verbal working memory). All data were analyzed to examine the task dependence of cortical gradients' topological properties. By employing the measures of network gradient dispersions as well as networks centroid distances, we revealed that alterations specific to each task occurred in topological properties of gradients involving both transmodal and unimodal networks, such as the executive control network varying between each task condition and the resting‐state condition. This work highlights the promise of applying cortical gradients to task‐based fMRI data, revealing the condition‐sensitive nature of certain cortical gradients' topological properties.

Iron is essential for neurophysiological health. Prior work has shown that subcortical tissue iron levels are the highest among all brain regions but also change over the lifespan. Recent functional MRI (fMRI) studies have provided evidence that an fMRI-derived iron-sensitive signal may index relative iron concentration in subcortical regions. In this context, we aimed to characterize the lifespan trajectory of this fMRI-derived iron-sensitive signal (relative iron quantification) in 10 subcortical regions and 14 thalamic nuclei from 881 healthy participants aged 12 to 88 years, using resting-state fMRI. Regressions were run with age as a predictor, separately for males (N = 429) and females (N = 452). The main results show non-linear effects of age, with an overall increase in iron levels across most subcortical regions within each sex. Six of the 14 thalamic nuclei in male participants had similar slopes of their lifespan iron levels, showing some homogeneity. The thalamic nuclei of female participants showed less agreement in slopes. This study provides new insight into the typical trajectory of iron levels across all major subcortical regions throughout the lifespan.

The number of individuals aged 60 years and older will reach a new global high in 2030 and is projected to continue increasing thereafter (Grinin et al., 2023). With this, research on healthcare, age-related disorders, and mental health in aging has increased. Anxiety disorders are among the most common mental health disorders worldwide (Javid et al., 2023). Accumulating evidence has further suggested that the presentation and symptoms of anxiety likely differ across the lifespan and by sex (Bryant et al., 2013;Shafiee et al., 2024). While rates of most anxiety disorders are reported to decrease with age, rates of generalized anxiety disorder (GAD) have similar rates in both younger and older adults (Andreescu & Lee, 2020). Roughly half of the GAD cases reported in older adults have an onset after 50 years of age (Andreescu & Lee, 2020) and show mixed results on whether prevalence differs by sex (Wolitzky-Taylor et al., 2010;Zhang et al., 2015). Given this, we will focus on GAD within the context of later life stages for this opinion and include some discussion of sex effects when relevant.The presence of clinically relevant anxiety symptoms in older adults has been estimated to vary between 15% and 56% within medical settings (Bryant et al., 2008). Additionally, a recent meta-analysis on studies that implemented anxiety measures specific to geriatric populations (the Geriatric Anxiety Scale and Geriatric Anxiety Inventory), estimated that roughly 25% of older adults experience some degree of anxiety symptoms (Shafiee et al., 2024). Anxiety symptoms in older age have a number of comorbidities including cognitive decline, poorer quality of life, cardiovascular issues, and other mental health issues, especially depression (Andreescu & Lee, 2020;Creed et al., 2002;Dotson et al., 2014;Lenze & Wetherell, 2011;Wolitzky-Taylor et al., 2010). With this, there is a pressing need to better understand the neurological mechanisms behind anxiety disorders at each stage of life. Given that age significantly impacts many other brain systems such as those responsible for executive functioning (Patil et al., 2021) and emotional regulation (Almdahl et al., 2021), there is a pressing need to also better understand the impact of age on the mechanisms linked to high anxiety levels as they may differ throughout the lifespan (see our opinion on that topic in the next section). Neuroimaging techniques provide noninvasive insights into such neural structure and function. In the last 15 years, the number of magnetic resonance imaging (MRI) studies has exploded with a progressive improvement in signal to noise (SNR) ratio, including better spatial and temporal resolutions, which has led to more reliable findings. However, due to the high number of publications, challenges remain in regard to the reproducibility of these neuroimaging findings, and one should remain critical until results can be robustly reproduced, regardless of sequences, head motion, or scanners. Due to the prevalence of neuroimaging research using MRI, we chose to focus on structural and functional (fMRI) MRI findings. In this context, for this special research topic celebrating the 15 th anniversary of Frontiers in Psychiatry, we plan to summarize different and specific aspects of MRI literature from the last 15 years, related to anxiety with a focus on late stages of life. We aim to highlight both the major discoveries made as much as the major challenges that remain to be further investigated. Academic search engines were used to find articles with the following inclusion criteria: must implement MRI measures, be published in the specified timeframe, and investigate some form of anxiety/late-life GAD. While this is far from an exhaustive review, we hope that this opinion will be an eye-opener that provides some guidance and suggestions for the future research of the next 15 years.Already 10 years ago, Andreescu and Varon (2015) noted a lack of neuroimaging research for late-life anxiety/GAD compared to younger populations, particularly for structural imaging. This was further highlighted by a review from Kolesar et al. (2019) that covered brain structural and functional abnormalities in individuals with GAD, regardless of age. This review noted overall structural neural abnormalities in individuals with GAD, including smaller hypothalamic (Terlevic et al., 2013) and hippocampal gray matter volumes (GMV; Moon et al., 2014;Moon & Jeong, 2017), larger amygdala GMV (Etkin et al., 2009), and larger white matter volume in the dorsolateral prefrontal cortex (dlPFC; Moon & Jeong, 2017). However, of the 85 studies included in the review, only eight had older adult participants and only two of these reported structural differences associated with GAD. Both studies included small sample sizes and did not investigate for sex-related effects. The first of these studies, from Mohlman et al. (2009), found that the volume of the medial orbitofrontal cortex (OFC) had a positive association with worry in those with GAD, but not in asymptomatic peers within a sample of 30 older adults aged 60 to 77. The second structural study by Andreescu et al. (2017) included a sample of 59 older adults and found that those with GAD had higher mean diffusivity (MD) in the white matter of the left pallidum and lower MD in the left middle fronto-orbital gyrus. In addition to this, those with GAD had less cortical thickness in the medial OFC and left rostral ACC, and smaller volume of the right inferior frontal gyrus. Unfortunately, none of the results in this study survived corrections for multiple comparisons. With this, moderate to large effect sizes (ranging from 0.54 to 1.06) were noted from the results, leading the researchers to suggest that a larger sample might be able to confirm these results.The Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) collaboration seeks to ameliorate the issue of small sample sizes through worldwide, multi-site...

Developmental Language Disorder (DLD) is a neurodevelopmental disorder characterized by limitations in learning, understanding, and using language. Magnetic Resonance Spectroscopy (MRS) studies are very limited, and it remains unknown to what degree the levels of GABA+ (“GABA+/tCr”) in the left inferior frontal cortex, supporting language, are impacted in this disorder. We recruited 14 children with DLD and 19 typically developing (TD) children. We also investigated the association between GABA+/tCr and language scores. Our results found a significant sex-by-group interaction, showing that male children with DLD have higher levels than the other groups. In addition, we reported a negative relationship between GABA+/tCr levels and language production scores in TD, but the inverse in children with DLD. This pilot study using MRS provides initial evidence that boys with DLD may experience upregulated inhibitory signaling and possible excitatory-inhibitory imbalance in one major brain hub supporting language function. Overall, these preliminary findings may implicate impaired inhibitory neurotransmission in the language brain system as a component of DLD.

The volume of the pituitary gland (PG) is impacted by both age and sex. However, their respective impact on the anterior and posterior lobes of the PG (APG and PPG) remains unclear, despite known distinctions in their neuroendocrinal roles. In this context, we investigated the impact of age and sex on the volume of each PG lobe across healthy adulthood. Lastly, we also tested whether perceived stress was influenced by the volumes of the APG and/or PPG and if the effects varied by age or sex. Results showed that older adults had a smaller APG but a larger PPG, compared to the younger adults. Women had a larger APG than men. Lastly, a main negative effect of PPG and an interaction between age-group and APG were reported on stress level, with the younger adults showing a negative association while the older adults had a positive association. Overall, we demonstrated that each PG lobe shows a different sex effect and age-related trajectory, with each having a different modulation on stress. This work underscores the need to examine the distinct roles of APG and PPG in the context of healthy and pathological aging.

Working memory is an important cognitive process that develops throughout early life. During adolescence, there is marked improvement in this process that is associated with structural and functional brain changes. These changes have been linked to age; however, endogenous testosterone is thought to regulate structural and functional changes in the brain during puberty, with differential influences across adolescence into early adulthood. Thus, testosterone may have a direct impact on brain activity that is modulated by age. The current study aimed to examine this using a working memory functional magnetic resonance imaging (fMRI) task in adolescents and young adults. Saliva samples collected prior to scanning were assayed for endogenous testosterone levels. One hundred and forty-five typically developing participants (74 female), aged 12–25 yr, completed a working memory fMRI task. Results showed that, for the most difficult versus the 0back conditions, younger female participants (≤19) only had more deactivation in the anterior cingulate cortex with higher level of testosterone. In contrast, male participants showed increased activation in the precentral gyrus with higher testosterone, regardless of age. These findings indicate sex differences in how endogenous testosterone relates to the activity of different brain regions recruited during working memory. Furthermore, these associations vary across typical adolescent development.

Aging is accompanied by changes in brain architecture that alter the lateralization of functional networks. In this study, we examined how hemispheric specialization changes across the adult lifespan by analyzing resting-state fMRI and structural MRI data from 728 typical adults aged 18 to 88 years. Using the Language-and-Memory Network atlas, we quantified regional asymmetries in functional connectivity along the cortex’s principal gradient, and normalized regional volumes across 37 bilateral regions. We identified two distinct age-related asymmetry trajectories: one pattern revealed a bilateralization of language-dominant regions, while the other showed increasing leftward specialization in multimodal regions associated with memory and language. These opposing patterns emerged around midlife and were linked to performance in language production tasks. By integrating connectivity gradients, structural asymmetries, and behavioral data, our findings provide new evidence for a dual mechanism reshaping functional brain lateralization with age and demonstrate the utility of resting-state metrics in tracking these shifts.

There is a spike in reward sensitivity during adolescence. Delay discounting involves subjective valuation of a reward in context of when it is gained. This study sought to assess if dynamic functional connectivity between the cognitive control network and the amygdala could predict delay discounting in adolescents and young adults. 448 participants were separated into three age groups, including younger and older adolescents and young adults. A sliding‐window approach was used to calculate dynamic functional connectivity between the left/right amygdala and the cognitive control network. Hierarchical models were run for each age group to determine if dynamic functional connectivity could predict delay discounting behavior in two delayed amount conditions above and beyond age and sex. Results showed that dynamic functional connectivity between the left, but not the right, amygdala and cognitive control network significantly predicted delay discounting in the larger amount condition for older adolescents. No significant results were found for the smaller amount condition in older adolescents or either condition in younger adolescents or adults. Stronger dynamic functional connectivity indicated a preference for immediate rewards during a larger amount condition in older adolescents only.

Childhood and adolescence are sensitive periods for the refinement of increasingly complex executive and social functions. A particularly important skill is the ability to navigate and interpret interpersonal relationships, which is reflected in part by the maturation of distributed resting networks. However, the relationships between negative social perceptions in youth and long-term alterations in between-network connectivity are limited. To partially address this gap, we utilized longitudinal resting-state functional magnetic resonance imaging (N = 93) with social pain measures from the NIH Toolbox Emotion Battery to determine the links between negative social perceptions on the trajectory of connectivity between the salience, frontoparietal, and default mode networks in the triple network model of psychopathology. Higher scores of perceived hostility, but not perceived rejection, tended to increase functional connectivity between the salience and both frontoparietal and default mode networks over time. These results suggest that more direct forms of threat (hostility) may be more impactful than rejection (limited desired social interactions), highlighting the importance of a dimensional approach to understanding developmental trajectories. While these connectivity changes align with several aberrant connectivity signatures observed across mental health disorders, these phenotypes are not pathognomonic of psychopathology and may reflect adaptive mechanisms in the context of social adversity.