Aberrant Maturation of the Uncinate Fasciculus Follows Exposure to Unpredictable Patterns of Maternal Signals

Abstract

Across species, unpredictable patterns of maternal behavior are emerging as novel predictors of aberrant cognitive and emotional outcomes later in life. In animal models, exposure to unpredictable patterns of maternal behavior alters brain circuit maturation and cognitive and emotional outcomes. However, whether exposure to such signals in humans alters the development of brain pathways is unknown. In mother-child dyads, we tested the hypothesis that exposure to more unpredictable maternal signals in infancy is associated with aberrant maturation of corticolimbic pathways. We focused on the uncinate fasciculus, the primary fiber bundle connecting the amygdala to the orbitofrontal cortex and a key component of the medial temporal lobe-prefrontal cortex circuit. Infant exposure to unpredictable maternal sensory signals was assessed at 6 and 12 months. Using high angular resolution diffusion imaging, we quantified the integrity of the uncinate fasciculus using generalized fractional anisotropy (GFA). Higher maternal unpredictability during infancy presaged greater uncinate fasciculus GFA in children 9-11 years of age (n = 69, 29 female). In contrast to the uncinate, GFA of a second corticolimbic projection, the hippocampal cingulum, was not associated with maternal unpredictability. Addressing the overall functional significance of the uncinate and cingulum relationships, we found that the resulting imbalance of medial temporal lobe-prefrontal cortex connectivity partially mediated the association between unpredictable maternal sensory signals and impaired episodic memory function. These results suggest that unbalanced maturation of corticolimbic circuits is a mechanism by which early unpredictable sensory signals may impact cognition later in life. Significance StatementOur prior work across species demonstrated that unpredictable patterns of maternal care are associated with compromised memory function. However, the neurobiological mechanisms by which this occurs in humans remain unknown. Here, we identify an association of exposure to unpredictable patterns of maternal sensory signals with the integrity of corticolimbic circuits involved in emotion and cognition using state-of-the-art diffusion imaging techniques and analyses. We find that exposure to early unpredictability is associated with higher integrity of the uncinate fasciculus with no effect on a second corticolimbic pathway, the cingulum. The resulting imbalance of corticolimbic circuit development is a novel mediator of the association between unpredictable patterns of maternal care and poorer episodic memory.

Early Life Adversity in Male Mice Sculpts Reward Circuits

“…In a study of children, increased generalized FA of the uncinate fasciculus, connecting amygdala to the orbitofrontal cortex, was associated with high maternal unpredictability. (Granger et al, 2021). While these global analyses examined multiple brain circuits, including reward circuits, the findings are consistent with abnormal structural maturation after ELA.…”

Early experience unpredictability in child development as a model for understanding the impact of the COVID-19 pandemic: A translational neuroscience perspective

“…For example, in the cross-species study of Davis et al (2017) , the findings from human sample indicate that early exposure to fragmented and unpredictable maternal signals (indexed via an entropy rate) is related to children’s poor hippocampus-dependent recall memory, drawing parallels to the animal findings in the same study. The impact of unpredictability on aberrant corticolimbic maturation has also been supported by Granger et al (2021) , indicating that exposure to unpredictable maternal sensory signals during infancy is associated with an imbalance of medial temporal lobe-prefrontal cortex connectivity (i.e., greater uncinate fasciculus coupled with decreased hippocampal cingulum generalized fractional anisotropy) in children 9–11 years of age. This study further suggests that such aberrant and imbalanced corticolimbic maturation mediates the associations between unpredictable maternal signals and children’s impaired episodic memory function.…”

“…The Questionnaire of Unpredictability in Childhood (QUIC) developed by Glynn et al (2019) also uses retrospective reports to capture unpredictability exhibited in parental monitoring and involvement, parental predictability, parental environment, physical environment, as well as safety and security. Additionally, laboratory-based or home-based observation paradigms are usually used to assess unpredictable parenting behaviors ( Davis et al, 2017 , Granger et al, 2021 , Noroña-Zhou et al, 2020 ).…”

“…These rodent findings have informed unpredictability research among humans. In parallel to animal models, several human studies have focused on unpredictable maternal sensory signals (typically obtained through coded mother-child dyadic interaction in a free play task) in relation to neural alternations and changes in child neurocognitive development ( Davis et al, 2017 , Granger et al, 2021 , Noroña-Zhou et al, 2020 ). In addition to unpredictable caregiving, a few studies have also examined the neurobiological influence of other unpredictability forms, such as household chaos ( Brown et al, 2019 , Brown et al, 2021 , Schreier et al, 2014 , Tarullo et al, 2020 ) and financial instability ( Brown et al, 2019 ).…”

“…To date, animal studies in this field of research have been mainly focusing on the neural and neuroendocrine alterations induced by fragmented and unpredictable maternal signals using the LBN poverty-simulating experimental paradigm (e.g., Baram et al, 2012 ; Bolton et al, 2018 ; Davis et al, 2017 ; Molet et al, 2016a ). A close translational model of this animal LBN paradigm in human studies assesses unpredictable maternal care in naturalistic observations of mother-child interactions and examines its underlying neural alterations ( Davis et al, 2017 , Granger et al, 2021 ). In addition to unpredictable maternal signals, the investigation of unpredictability in human studies has also been looking into other forms of unpredictable early experiences, such as household chaos and financial instability, in relation to their neuroendocrine and immune underpinnings (e.g., Brown et al, 2019 , Brown et al, 2021 ; Raver et al, 2015 ).…”