Integrity of the uncinate fasciculus is associated with emotional pattern separation-related fMRI signals in the hippocampal dentate and CA3

Abstract

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders that involve disruptions in emotional processing. One such pathway -the uncinate fasciculus (UF) -connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity between the medial temporal lobes and the orbitofrontal cortex remains unknown. Here we ask the question of whether the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution functional MRI, we found that reduced integrity of the UF is related to higher activation in the DG/CA3 subregions of the hippocampus during an emotional pattern separation task. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that hyperexcitability in this network (which may be driven by CA3 recurrent collaterals) is associated with memory errors and that the UF may allow the OFC to exert inhibitory control on this network and improve discrimination of emotional experiences. This work provides novel mechanistic insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional memory..

General additive models address statistical issues in diffusion MRI: An example with clinically anxious adolescents

“…We note that these test statistics did not survive a Bonferroni correction despite decent effect sizes, and so while we will interpret them it is possible that we are merely capitalizing on noise. The detection of the left uncinate association with memory generalization relates to recent work by Granger et al, ( Granger et al, 2021 ), who demonstrated in an identical eMST paradigm that only differences in uncinate diffusion metrics were associated with medial temporal processes during correct lure discrimination. Where Granger et al, ( Granger et al, 2021 ) did not detect a relationship between uncinate integrity and lure discrimination, however, we demonstrate a group left uncinate FA interaction during negative lure generalization.…”

“…The detection of the left uncinate association with memory generalization relates to recent work by Granger et al, ( Granger et al, 2021 ), who demonstrated in an identical eMST paradigm that only differences in uncinate diffusion metrics were associated with medial temporal processes during correct lure discrimination. Where Granger et al, ( Granger et al, 2021 ) did not detect a relationship between uncinate integrity and lure discrimination, however, we demonstrate a group left uncinate FA interaction during negative lure generalization. This interaction is interesting as (a) the High anxiety group had significantly larger FA values ( Fig.…”

“…By default pyAFQ generates a set of 18 tracts and, given the aims of the parent R01 ( McMakin et al, 2021 ), three pathways were selected for modeling and testing: the left uncinate fasciculus, the right uncinate fasciculus, and the anterior forceps. The left and right uncinate were selected for their connection with sleep, anxiety, development, and potential link with memory ( Jamieson et al, 2021 , Granger et al, 2021 ), while the anterior forceps were selected as a control region due to its similarity in curvature with the uncinate fasciculi ( Fig. 1 ).…”

Immature excitatory neurons in the amygdala come of age during puberty

“…The parahippocampal cingulum in particular is involved in emotional processing and episodic memory, and structural abnormalities are observed in MDD, autism spectrum disorders (ASD), obsessive compulsive disorder (OCD), and schizophrenia ( Bubb et al, 2018 ). The uncinate fasciculus also plays a role in anxiety ( Modi et al, 2013 ), depression ( Zhang et al, 2012 ), and emotional pattern separation ( Granger et al, 2021 ), a function we will discuss in more detail in the following section ( Section 4.2 ). PL connectivity with the hippocampus, other amygdala nuclei, and potentially other brain regions - possibly via the uncinate fasciculus and/or the cingulum - places this region as an important node in emotional circuits.…”

“…Work in mice shows that discrete populations of neurons within the BLA encode cues of innate or learned negative vs. positive valence ( Beyeler et al, 2018 ), and negative stimuli can be relearned as positive and vice versa ( Zhang and Li, 2018 ). Interestingly, hippocampal-amygdala connectivity and the uncinate fasciculus are important for emotional pattern separation ( Granger et al, 2021 , Zheng, 2019 ). The possible involvement of the PL in connectivity between the hippocampus and the amygdala and emotional flexibility also raises the question of how late-maturing neurons in the PL may be relevant to neuropsychiatric disorders, especially those involving emotional dysregulation.…”