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Systems/Circuits
Aberrant Maturation of the Uncinate Fasciculus Follows
Exposure to Unpredictable Patterns of Maternal Signals
Steven J. Granger,
1,2
Laura M. Glynn,
3
Curt A. Sandman,
4
Steven L. Small,
5
Andre Obenaus,
6
David B. Keator,
4
Tallie Z. Baram,
1,6,7
Hal Stern,
8
Michael A. Yassa,
1,2,4
and Elysia Poggi Davis
4,9
1
Center for the Neurobiology of Learning and Memory, University of California, Irvine, California 92697,
2
Department of Neurobiology and
Behavior, University of California, Irvine, California 92697,
3
Department of Psychology, Chapman University, Orange, California 92866,
4
Department of Psychiatry and Human Behavior, University of California, Irvine, California 92697,
5
School of Behavioral and Brain Sciences,
University of Texas at Dallas, Richardson, Texas 75080,
6
Department of Pediatrics, University of California, Irvine, California 92697,
7
Department
of Anatomy and Neurobiology, University of California, Irvine, California 92697,
8
Department of Statistics, University of California, Irvine,
California 92697, and
9
Department of Psychology, University of Denver, Denver, Colorado 80208
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 unpre-
dictable maternal sensory signals and impaired episodic memory function. These results suggest that unbalanced maturation of cor-
ticolimbic circuits is a mechanism by which early unpredictable sensory signals may impact cognition later in life.
Significance Statement
Our 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 ex-
posure to early unpredictability is associated with higher integrity of the uncinate fasciculus with no effect on a second corti-
colimbic 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.
Introduction
Experiences occurring during sensitive periods in early life are
powerful factors influencing brain development and cognition
(Hasler et al., 2004;Andersen and Teicher, 2008;Short and
Baram, 2019). Although it is clear that the quality of maternal
care affects the risk for offspring psychological disorders and
neurobiological changes later in life (Bowlby, 1950;Lebel et al.,
2016;Glynn and Baram, 2019), less is known about how patterns
of maternal behavior impact human development (Baram et al.,
2012;Davis et al., 2017). Recent work has indicated that
Received Feb. 17, 2020; revised Nov. 25, 2020; accepted Dec. 2, 2020.
Author contributions: S.J.G., L.M.G., C.A.S., S.L.S., T.Z.B., M.A.Y., and E.P.D. designed research; S.J.G.,
L.M.G., C.A.S., S.L.S., A.O., and E.P.D. performed research; A.O., D.B.K., and H.S. contributed unpublished
reagents/analytic tools; S.J.G. analyzed data; S.J.G., M.A.Y., and E.P.D. wrote the paper.
This work was supported by the National Institute of Health (Grant P50-MH-096889 (Principal Investigator:
T.Z.B.); Grant R01-MH-102392 (Principal Investigator: M.A.Y.); Grant R03-MH-086062 (Principal Investigator:
E.P.D.); Grant NS-41298 (Principal Investigator: C.A.S.); Grant HD-51852 (Principal Investigator: C.A.S.); and
Grant HD-28413 (Principal Investigator: C.A.S.).
The authors declare no competing financial interests.
Correspondence should be addressed to Michael A. Yassa at myassa@uci.edu or Elysia Poggi Davis at
Elysia.Davis@du.edu.
https://doi.org/10.1523/JNEUROSCI.0374-20.2020
Copyright © 2021 the authors
1242 •The Journal of Neuroscience, February 10, 2021 •41(6):1242–1250
unpredictable patterns of maternal sensory signals during
infancy are a novel contributor to impaired cognitive and emo-
tional functions later in life (Chen and Baram, 2016;Molet et
al., 2016b;Walker et al., 2017;Glynn and Baram, 2019;
Noraña-Zhou et al., 2020).
We previously reported in both humans and rodents that ex-
posure to greater unpredictable sensory signals during infancy is
associated with memory deficits later in life (Ivy et al., 2008,
2010;Molet et al., 2016a;Bath et al., 2017;Davis et al., 2017). In
rodents, pup exposure to unpredictable maternal behavior leads
to abnormal maturation of brain circuits involved with memory
(Brunson et al., 2005;Ivy et al., 2010;Guadagno et al., 2016;
Molet et al., 2016a;Walker et al., 2017). Whether the same corti-
colimbic circuits are impacted by unpredictable maternal sensory
signals in humans remains unknown.
Across species, aberrant maturation of amygdala–prefrontal
circuits is well recognized as a key outcome of exposure to
stress (Burghy et al., 2012;Gee et al., 2013;Chen and Baram,
2016;Tottenham and Galván, 2016;Burgos-Robles et al.,
2017). Accelerated maturation of amygdala–prefrontal cortex
(PFC) functional connectivity may be an adaptive response to
early life adversity, which reprioritizes developmental goals to
match the demands of adverse early life environments (Gee et
al., 2013). In humans, the predominant anatomic connection
between these two regions is the uncinate fasciculus (UF;
Ebeling and von Cramon, 1992). The uncinate is thought to be
important for episodic memory and has recently been
hypothesized to play an important role in adjudicating among
competing memory representations during retrieval (Von Der
Heide et al., 2013;Alm et al., 2016). Abnormal development of
the uncinate could lead to impairments in cognitive and emo-
tional functions (Carballedo et al., 2012;Zhang et al., 2012;
Vilgis et al., 2017;Yang et al., 2017;Bhatia et al., 2018).
Abnormal development of the uncinate has been associated
with early life adversity including a history of institutionaliza-
tion during childhood and paternal depressive symptoms
(Eluvathingal et al., 2006;Govindan et al., 2010;Hanson et al.,
2015;Ho et al., 2017;El Marroun et al., 2018).
Here, we evaluated whether exposure to unpredictable mater-
nal signals in infancy is associated with uncinate integrity, meas-
ured between the ages of 9 and 11 years. To determine whether
the observed effects were specific to the uncinate or are general
features of corticolimbic white matter, we conducted similar
analyses in the hippocampal cingulum, which shares the fronto-
temporal connectivity of the uncinate but is spatially distinct
(Bubb et al., 2018). As the functional output of brain circuits is a
combinatorial sum of the activity of each of their components
(Redish and Gordon, 2017), we also conducted analyses using
the ratio of uncinate to hippocampal cingulum connectivity as a
measure of imbalance across these two pathways.
To determine the behavioral relevance of changes in white
matter connectivity associated with unpredictable maternal sen-
sory signals, we focused on episodic memory function, which we
assessed by using the mnemonic similarity task (MST), a well
validated task (Stark et al., 2019) that is sensitive to the ability
of the hippocampus to discriminate among highly similar expe-
riences (i.e., pattern separation), which is thought to be a core
facet of episodic memory (Marr, 1971;Yassa and Stark, 2011;
Leal and Yassa, 2018;Leutgeb et al., 2007). This task was chosen
as we have previously shown across species that greater unpre-
dictability of maternal sensory signals in infancy is associated
with differences in memory function (Davis et al., 2017).
Further, MST performance is dependent on successful
adjudication among competing memory representations during
retrieval, which is thought to be a core function of the uncinate
fasciculus (Von Der Heide et al., 2013;Alm et al., 2016).
Materials and Methods
Participants
Asampleof73mother–offspring dyads (n=30females) from aprospec-
tive, longitudinal, prenatal cohort participated. Initial maternal recruit-
ment criteria included the following: English-speaking, .18 years old,
nonsmokers, no evidence of drug/alcohol use, and singleton pregnancy.
Unpredictable maternal sensory signals were assessed when the infants
were 6 and 12months of age, and the children participated in a single
MRI scan between 9 and 11 years of age. Demographic information for
the full sample of participants is summarized in Table 1.
Measurement of unpredictability of maternal sensory signals
Coding maternal sensory signals. Unpredictable maternal sensory
signals were coded from a free play dyadic interaction between a mother
and her child, as described in the study by Davis et al. (2019).Briefly,
mothers were video recorded interacting with their child in a semistruc-
tured 10 min play episode at 6 and 12 months of age. Mothers were given
a standard set of age-appropriate toys and instructed to interact with
their infants naturally as if they were at home. Behaviors from the
mother that provided auditory, visual, or tactile sensory signals to the
child were coded on a moment-to-moment basis from the video record-
ings using The Observer XT 11 (Noldus). Auditory signals included all
maternal vocalizations, visual signals included maternal manipulation of
toy or object while the infant was visually attending, and tactile signals
involved all instances of physical contact (holding/touching) initiated by
the mother. Coders were blind to all other information on study partici-
pants. Interrater reliability was calculated based on 20% of videos and
averaged 89% (Davis et al., 2017).
Quantifying unpredictability of maternal sensory signals. Unpredictability
of maternal sensory signals were quantified by calculating the entropy
rate of the sequences of visual, tactile, and auditory maternal signals
assessed during the two 10 min naturalistic observation periods
described above. The entropy rate is determined as follows. We first
identify all transitions among visual, tactile, and auditory maternal sig-
nals, accounting for all possible combinations of the different types of
sensory signals. As an example, if a mother was speaking (auditory) to
her child and then shows her a toy (visual) while labeling it (auditory),
this would be classified as a transition from auditory only to auditory
Table 1. Sample characteristics for mother/infant dyads (N= 73)
Characteristics Values
Maternal characteristics
Cohabitation status (% married or cohabitating) 84.9
Education, years (SE) 16 (0.4)
Education (%)
High school or less 11.1
Some college, associate degree, or vocational degree 28.7
4 year college degree 28.8
Graduate degree 23.3
Maternal race/ethnicity (%)
White/European/North African/Middle Eastern 49.3
Asian 12.3
Hispanic white 30.1
Multiethnic/other 8.2
Maternal depression/anxiety (mean 6SE)
STAI 17.2222 60.641
EPDS 4.95 60.612
Maternal sensitivity (mean 6SE) 9.85 60.12
Income to needs ratio (mean 6SE) 509.36 659.5
Maternal unpredictable sensory signals (mean 6SE) 0.81 60.018
Age at MRI scan (mean 6SE) 9.92 60.078
Sex 43 males, 30 females
Days between scan and MST completion 99 612.14
Granger et al. ·Uncinate and Patterns of Maternal Sensory Signals J. Neurosci., February 10, 2021 •41(6):1242–1250 •1243
and visual. The resulting transitions are then
modeled as changes in the state of a discrete-
state first-order Markov process and the en-
tropy rate of that process calculated as
described in the study by Davis et al. (2017).
We considered alternative strategies for cal-
culating the entropy rate (e.g., based on other
Markov chain models; second order and third
order) as well as a nonparametric approach
based on theoretical results relating data
compression to unpredictability of maternal
sensory signals and found that results were
highly consistent (Spearman’s rank correla-
tions for resulting unpredictability measures
ranging from 0.91 to 0.98; Vegetabile et al.,
2019). The entropy rate measurement can be
thought of as capturing how random or
uncertain a mother’s next behavior would
seem to someone making a guess based on
previous observed behavior. Entropy rate can
range from 0 (transitions are perfectly pre-
dictable, e.g., speech is always followed by
touch) to a maximum of 2.807 (unpredict-
able, the next observed behavior among them
appears to occur at random). The resulting
unpredictability rates were calculated sepa-
rately for each visit (at 6 and 12 months) and
averaged. A comprehensive description of the
calculation regarding maternal unpredictabil-
ity and the entropy rate quantification is
described in the study by Davis et al. (2019), and an R package for the
calculation of entropy is available at https://contecenter.uci.edu/
shared-resources.
Episodic memory: mnemonic similarity task. The MST was adminis-
tered on average 99 612.13 d from the date of the MRI scan. The MST
consists of the following two phases: an incidental encoding phase and a
surprise memory test (Fig. 1). During the incidental encoding phase,
children are presented with a series of objects appearing on the screen
for 2.0 s (interstimulus interval, 0.5 s). At this time, the children were
asked to rate the objects as being found “indoor”or “outdoor”via
computer keyboard presses. A total of 64 images was presented dur-
ing the testing phase. During the retrieval (testing) portion, children
were presented with 32 target images (identical images that
appeared during encoding), 32 foil images (images that did not
appear during encoding), and 32 lure images (variants of images
presented during encoding). During the test, children were asked to
indicate whether the presented object was “old”(they had seen the
image before), “similar”(the images were slightly different from
images presented during the test), or “new”(images were novel and
not seen during the test). Lure items were varied by similarity rat-
ings on a scale from 1 to 5 with 1 being the most similar (bin 1: most
difficult to discriminate) and 5 being the least similar (bin 5: easier
to discriminate). Lure items were distributed across bin similarity in
the following way: bin 1 (6 items), bin 2 (7 items), bin 3 (7 items),
bin4(6items),andbin5(6items).Asmeasuresofperformance,we
calculated a lure discrimination index (LDI), which is defined as the
probability of indicating similar when given a lure minus the proba-
bility of indicating similar given a foil. In this fashion, this measure
controls for response bias (indicating similar for every item). The
LDI is used as the index of episodic memory. We analyzed the low-
similarity conditions (average, L4 and L5) as previous research using
the MST demonstrated that children this age exhibit chance-level per-
formance on the more difficult high-similarity conditions (Rollins
and Cloude, 2018). A significant advantage of the MST task is the
concurrent ability to assess traditional recognition memory by evaluat-
ing the recognition of target items versus novel foils. We used perform-
ance on this recognition condition as a control to determine the
specificity of the relationship between hippocampal pattern separation
and unpredictable maternal sensory signals.
Measurement of possible confounding variables.
To assess whether associations with unpredictable maternal sensory
signals are influenced by confounding factors, we evaluated maternal
mental health, quality of maternal care, and household income. These
variables are further described below.
Maternal depression/anxiety. Symptoms of maternal depression and
anxiety were assessed at the two postnatal visits (at 6 and 12months).
The Edinburgh Postnatal Depression Scale (EPDS; Cox et al., 1987)and
StateAnxietyInventory(STAI;Spielberger et al., 1983) were adminis-
tered. Scores were standardized and then averaged as an index of mater-
nal mental health (Davis et al., 2019).
Quality of maternal care: maternal sensitivity. To determine whether
the unpredictability of maternal signals was associated with brain out-
comes beyond more standard measures of quality of maternal care, we
evaluated a measure of maternal sensitivity during the same observation
period as the quantification of maternal unpredictability. Maternal sensi-
tivity was coded using a protocol developed for the Eunice Kennedy
Shriver National Institute of Child Health and Human Development
(NICHD) Study of Early Child Care and Youth Development (NICHD
Early Child Care Research Network, 1999). Maternal behavior was eval-
uated for sensitivity to nondistress, intrusiveness (reverse scored), and
positive regard (1 = not at all characteristic to 4 = highly characteristic).
A sum of ratings of sensitivity were calculated and used according to the
NICHD Early Child Care Research Network (1999).
Income-to-needs ratio. The income-to-needs ratio (INR) was deter-
mined by comparing household income to the federal poverty line for a
given year and a given household size. Ratios ,1.00 indicate that house-
hold income is below the federal poverty line; in contrast, a ratio of
1.00 indicates income above the federal poverty level (Grieger et al.,
2009).
Diffusion imaging protocol and processing
MRI were collected on a 3.0 tesla Philips Achieva scanner at the
Neuroscience Imaging Center at the University of California, Irvine,
using a 32-channel head coil. The diffusion-weighted imaging scheme
consisted of six separate runs of 11 volumes (including one b = 0 vol-
ume) each. The first two runs were collected using a b value of
500 s/mm
2
, the third and fourth runs were collected using a b value of
1000 s/mm
2
, and the fifth and sixth runs were collected using a b
value of 2000 s/mm
2
. Thus, the final scan consisted of a multishell
Figure 1. The MST consists of two phases: an incidental encoding phase and a retrieval (testing) phase. The incidental
encoding phase consists of a series of 64 images where children are asked to indicate whether the items would appear
indoor or outdoor. Upon completion of the incidental encoding phase, children completed the retrieval or testing portion of
the MST. During test, children were presented with 32 target images (identical images that appeared during encoding), 32
foil images (images that did not appear during encoding), and 32 lure images (variants of images presented during encod-
ing). Children were asked to indicate whether the presented object was “old”(they had seen the image before), similar (the
images were slightly different from images presented during test), or “new”(images were novel and not seen during test).
Lure items were varied by similarity ratings on a scale from 1 to 5, with 1 being the most similar (bin 1: most difficult to dis-
criminate) and 5 being the least similar (bin 5: easier to discriminate).
1244 •J. Neurosci., February 10, 2021 •41(6):1242–1250 Granger et al. ·Uncinate and Patterns of Maternal Sensory Signals
sequence with 60 noncollinear directions and six B0 volumes. The fol-
lowing scanning parameters were used: direction of acquisition was
anterior to posterior, the field of view was 216 (Anterior-Posterior),
216 (Foot-Head), 151.2 (Right-Left); the scan resolution was 108 (10),
127(y);numberofslices=84;voxelsize=1.691.68 1.68 mm;
TR = ;11 502.76; TE = 89. Raw data were corrected for motion and
eddy currents using FSLs eddy program (Andersson and Sotiropoulo,
2016). Data were analyzed using DSI-Studio (http://dsi-studio.
labsolver.org; July 26, 2017 build). Corrected data were then recon-
structed using the DSI-Studio Q-spin Diffeomorphic Reconstruction
(QSDR) function, which uses a powerful diffeomorphic algorithm to
warp model-free orientation distribution functions (ODFs) to
Montreal Neurologic Institute (MNI) space (Yeh and Tseng, 2011).
ODFs were reconstructed with the default diffusion sampling length
ratio of 1.25, which was sufficient to model crossing fibers at the
intersection of the corticospinal tract and corpus callosum. This value
was additionally validated by varying the diffusion sampling length
ratio at intervals of 0.2 and visually examining this intersection using
generalized q-sampling imaging. Other reconstruction parameters
included the following registration method: norm 7–9-7, eightfold
ODF tessellation, number of fibers resolved (5). Output resolution
was increased to 1 mm. Quality control for fit to the template space
was implemented by setting a criterion on R
2
at .0.6. Four subjects
of the total of 73 were eliminated based on these criteria, leaving a
final sample size of 69 subjects (29 females). Subject head motion was
assessed by the eddy_movement_rms file exported from eddy (move-
ment relative to the previous volume) and included as a nuisance
regressor. Subject T1-weighted images were used for the quantifica-
tion of intracranial brain volume. Structural MPRAGE scans were
collected at the time of the diffusion scan with the following parame-
ters: 1 mm isotropic resolution; 208 sagittal slices; field of view = 208
256 256 mm; flip angle = 8°; TR = 8 ms; TE = 3.7 ms; matrix size =
256 210 mm. Intracranial volume was calculated using Freesurfer ver-
sion 6.0 and used to rule out whether differences in GFA were because of
intracranial volume.
Region of interest-based approach
Masks of regions of interest (ROIs) were obtained through the Johns
Hopkins white matter atlas (in MNI space), which is available within
DSI Studio. Regions included limbic white matter regions, namely, the
uncus of the uncinate fasciculus and the hippocampal cingulum bilater-
ally. Averaged generalized fractional anisotropy (GFA) values were
extracted for each ROI and averaged across hemispheres. GFA is one of
several model-free diffusion measures and is known to correlate with
fractional anisotropy of the tensor model. GFA was used to assess the
structural integrity of complex tissues in a clinical setting, particularly
when there are heterogeneous fiber tissues (Koh et al., 2018;Yamada et
al., 2018), and has been used in studies of affective disorders (Chiang et
al., 2016;Lo et al., 2017). However, it should be noted that the accuracy
of GFA depends on the type of tissue being evaluated as well as the b
value at which the raw data are collected (Tuch et al., 2002;Tuch, 2004;
Gorczewski et al., 2009;Fritzsche et al., 2010).
Statistical analysis
Covariates were identified based on theoretical links to either maternal
behavior or child outcomes. Covariates included in all analyses were
child sex, maternal depressive and anxiety symptoms, maternal sensitiv-
ity, and income-to-needs ratio. Correlational analysis was conducted
using Prism GraphPad 7 with two-tailed tests of Pearson correlation
coefficients. Multiple linear regression models were implemented using
RStudio to assess the association between unpredictable maternal sen-
sory signals and the integrity of the white matter tract (uncinate fascicu-
lus and hippocampal cingulum) after the consideration of covariates.
Mediation analyses were conducted using the “mediation”package in
RStudio. Each mediation model was tested using bias-corrected and
accelerated procedures with 10,000 simulations. One case of missing
data were imputed for the measurement of maternal depression and
anxiety using all possible covariates and uncinate fasciculus GFA
(Sinharay et al., 2001). Three cases of missing data were imputed for
INR in a similar manner using all possible covariates (including mater-
nal depression/anxiety and uncinate fasciculus GFA).
Results
Exposure to unpredictable maternal sensory signals during
infancy is associated with higher uncinate fasciculus integrity
at age 9–11 years
First, we tested the hypothesis that exposure to unpredictable
maternal sensory signals in infancy is associated with the integ-
rity of the uncinate fasciculus in 9- to 11-year-old children using
GFA as our primary outcome measure. Exposure to unpredict-
able maternal sensory signals during infancy predicted greater
UF GFA (r=0.37, p=0.0017; Fig. 2a). Multiple regressions with
covariates (maternal depression/anxiety, maternal sensitivity,
income-to-needs ratio, and sex) did not change the association
between unpredictable maternal sensory signals and UF GFA
(
b
=0.26,R
2
=0.35,p= 0.020; Table 2). Sex was significant as an
independent predictor of UF GFA. However, the sex by unpre-
dictability interaction was nonsignificant.
To rule out the possibility that age at scan and in-scanner
head motion (derived from eddy) were responsible for differences
Figure 2. Generalized fractional anisotropy results. A, A significant positive association between exposure to unpredictable maternal sensory signals during infancy and mean uncinate fasci-
culus GFA primarily in girls (r=0.44, p=0.016) 9–11 years of age. This association was not significant in boys (r=0.30, p=0.057). B, No association between exposure to unpredictable
maternal sensory signals during infancy and mean hippocampal cingulum GFA in girls (r=0.29, p= 0.13) or boys (r=0.15,p=0.35) 9–11 years of age.
Granger et al. ·Uncinate and Patterns of Maternal Sensory Signals J. Neurosci., February 10, 2021 •41(6):1242–1250 •1245
in UF GFA, we included them as nuisance regressors in an addi-
tional model with all previously mentioned covariates. The
association between unpredictable maternal sensory signals and
UF GFA (
b
= 0.26, R
2
= 0.38, p= 0.017) remained significant
after accounting for age and head motion. Additionally, neither
age, subject head motion, nor their interaction predicted UF
GFA. Additionally, intracranial volume did not predict UF
GFA (r=0.023, p= 0.85). Finally, including age and intracra-
nial volume (calculated from T1-weighted images) as covariates
in our analyses did not alter the statistical significance of the
relationships between unpredictable maternal sensory signals
and UF GFA.
Because the functional output of brain circuits is a combina-
torial sum of the activity of each of their components, we
conducted similar analyses in the hippocampal cingulum bundle,
a second component of the corticolimbic circuit that connects
the connects the medial temporal lobe (MTL) with the PFC via a
posterior pathway through the retrosplenial cortex (Bubb et al.,
2018). While unpredictable maternal sensory signals did not sig-
nificantly predict hippocampal cingulum GFA (r=0.0026,
p=0.98;Fig. 2b), the sex by unpredictability interaction was mar-
ginally significant (Table 3;
b
=1.22, R
2
= 0.052, p=0.086).
The directionality of the associations identified in the UF and
marginal interaction with sex in the cingulum prompted us to
ask whether the two findings are related to an imbalance in the
integrity or maturation of these two circuits. We calculated a sim-
ple ratio measure of UF/cingulum GFA to capture this imbalance.
We found a significant association between the unpredictability of
Table 3. Results of interaction model with unpredictability of hippocampal cingulum GFA predicted by unpredictability of maternal sensory signals, sex, and their
interaction
Regression model R
2
F
b
Standardized
b
SE (
b
)pvalue
Overall model 0.052 1.18
Unpredictability of maternal sensory signals 0.025 0.59 0.015 0.11
Sex 0.013 1.024 0.0084 0.12
Sex punpredictability 0.018 1.22 0.010 0.086
Figure 3. Results of UF/cingulum ratio analyses. A, Shows the statistically significant positive association between unpredictable maternal sensory signals and the ratio of anterior MTL–PFC
connectivity (uncinate fasciculus GFA) to posterior MTL–PFC connectivity (hippocampal cingulum GFA; r=0.28,p=0.018).B, The marginally significant association between a greater ratio of
anterior MTL–PFC connectivity to posterior MTL–PFC connectivity and impaired lure discrimination on low-similarity lure items (r=0.23, p=0.058).C,D, The results of the mediation analy-
ses.
b
values represent the coefficient for the arrows effect. c’represents the direct effect, and c represents the total effect of unpredictable maternal sensory signals on low-similarity lure dis-
crimination. C, Shows the significant indirect effect of the ratio of uncinate fasciculus GFA to hippocampal cingulum GFA mediating the association between unpredictable maternal sensory
signals and low similarity lure discrimination. D, The nonsignificant indirect effect of the ratio of uncinated fasciculus GFA to hippocampal cingulum GFA mediating the association between
unpredictable maternal sensory signals and recognition performance is statistically significant at p,.05.
Table 2. Unpredictability of maternal sensory signals related to increased uncinate fasciculus GFA accounting for possible covariates
Regression model R
2
F
b
Standardized
b
SE (
b
)pvalue
Overall model 0.35 6.73
Unpredictability of maternal sensory signals 1.34 10
2
0.26 5.62 10
3
0.020
Maternal depression anxiety 5.054 10
4
0.065 7.96 10
4
0.53
Maternal sensitivity 1.56 10
3
0.21 8.041 10
4
0.057
Income-to-needs ratio 1.01 10
6
0.066 1.60 10
6
0.53
Sex 6.30 10
3
0.39 1.67 10
3
0.00036
1246 •J. Neurosci., February 10, 2021 •41(6):1242–1250 Granger et al. ·Uncinate and Patterns of Maternal Sensory Signals
maternal sensory signals and the ratio of UF GFA to hippocampal
cingulum GFA (r= 0.28, p=0.018;Fig. 3a).
Corticolimbic circuit imbalance is associated with impaired
episodic memory performance
Based on prior work across species (Davis et al., 2017), we
hypothesized that the unpredictability of maternal sensory sig-
nals would be associated with worse performance on cognitive
tasks. In the current study, we used the LDI to assess episodic
memory performance. Interestingly, we observed that unpredict-
able maternal sensory signals did not significantly predict
impaired episodic memory performance (r=0.022,p=0.86).We
then probed whether the observed circuit changes related to
unpredictable maternal sensory signals were associated with epi-
sodic memory performance.
UF GFA was not significantly associated with episodic mem-
ory performance assessed with the LDI (r=0.091, p= 0.46).
However, we found that decreased hippocampal cingulum GFA
was marginally associated with lower LDI (r=0.22, p= 0.072). A
higher UF/cingulum GFA ratio was also marginally associated
with lower LDI (r=0.23, p= 0.058; Fig. 3b). The interaction
between sex and the UF/cingulum ratio in association with LDI
did not reach statistical significance (
b
=1.28,p=0.13).
We observed a significant indirect association through
which higher levels of unpredictable maternal sensory signals
was associated with a higher UF/cingulum GFA ratio, which,
in turn, was associated with worse LDI. In separate media-
tion models, neither UF GFA (indirect effect = 0.061, CI =
0.24 to 0.097, p= 0.44) nor cingulum GFA (indirect effect =
0.0008, CI = 0.088 to 0.11, p= 0.99) were significant media-
tors of the association between unpredictable maternal sensory
signals and LDI; however, the UF/cingulum GFA ratio mea-
sure was a marginally significant mediator of the association
between unpredictable maternal sensory signals and LDI
(indirecteffect=0.10, p=0.049,CI = 0.28 to 0.0081; Fig.
3c). Critically, this association was specific to lure discrimina-
tion and did not generalize to general recognition memory;
the indirect association was not statistically significant with
the recognition memory outcome (indirect effect = 0.063,
p= 0.31, CI = 0.27 to 0.034; Fig. 3d).
Discussion
There are three key findings of this study. First, we show that
infant exposure to unpredictable patterns of maternal-derived
sensory signals is associated with greater integrity of the uncinate
fasciculus in late childhood. Second, this finding is specific to the
uncinate fasciculus and is not present in the hippocampal cingu-
lum. Last, we find that the ratio of uncinate fasciculus (anterior
MTL–PFC connectivity) to hippocampal cingulum GFA (poste-
rior MTL–PFC connectivity; Fig. 4) mediates the association
between experiencing greater unpredictability of maternal sen-
sory signals and impaired performance on an episodic memory
task. Together, these data suggest that one possible consequence
of early life unpredictability is desynchronized maturation of two
key corticolimbic pathways resulting in selective impairments in
episodic memory tasks requiring nuanced and fine-tuned MTL–
PFC connectivity. Such findings are consistent with those of
Figure 4. Anterior and posterior MTL–PFC circuits in humans. The circuit schematic summarizes our results demonstrating that (1) the anterior MTL–PFC pathway (i.e., the uncinate fascicu-
lus in green lines), which connects the amygdala and rhinal cortex directly to the orbitofrontal cortex is enhanced in relationship to the increased unpredictability of maternal sensory signals
and (2) the posterior MTL–PFC pathway (i.e., the cingulum in red and white), which connects the hippocampus and rhinal cortex with the retrosplenial cortex as well as medial prefrontal and
orbitofrontal cortex is not related to the increased unpredictability of maternal sensory signals. These aberrations in circuitry are consistent with a developmental scenario, primarily in female
children 9–11 years of age, in which unpredictable maternal sensory signals bias connectivity in favor of the anterior pathway at the expense of the posterior pathway and possibly lead to epi-
sodic memory dysfunction.
Granger et al. ·Uncinate and Patterns of Maternal Sensory Signals J. Neurosci., February 10, 2021 •41(6):1242–1250 •1247
other studies, suggesting that these connections are vulnerable to
early life adversity (Gee et al., 2013;Tottenham and Galván,
2016).
Unpredictable maternal sensory signals have been identified
as a novel type of early life adversity, associated with reduced
memory and executive functioning (Davis et al., 2017,2019)an
association that has been observed in independent cohorts, such
as FinnBrain (Karlsson et al., 2018;Davis et al., 2019). Evidence
that patterns of sensory input contribute to the maturation of
brain pathways has been previously shown in rodents (Molet et
al., 2016a;Bolton et al., 2018) and affects emotional (Walker et
al., 2017) as well as cognitive circuits (Chen and Baram, 2016).
Here we provide evidence that corticolimbic circuits are associ-
ated with infant exposure to unpredictability from the mother in
early life and that imbalance among these circuits serves as a pos-
sible mechanism explaining differences in cognitive function
observed here and in previous studies (Davis et al., 2017,2019).
Past literature on the association of uncinate fasciculus with
various types of early life adversity report mixed results. For
example, several studies have found reductions in fractional ani-
sotropy associated with early life maltreatment and deprivation
(Eluvathingal et al., 2006;Govindan et al., 2010;Hanson et al.,
2015;Ho et al., 2017). In contrast, other studies reported
increased diffusion properties of the uncinate fasciculus in pre-
mature infants exposed to prenatal maternal stress (Lautarescu et
al., 2019) and among adults exposed to childhood trauma
(Tatham et al., 2016). Discrepancies may be because of differen-
ces in the type of adversity and developmental stage at assess-
ment, and none of these prior studies evaluated unpredictability.
We focus on unpredictability as a type of early adversity that has
been associated with long-term consequences for development
(Glynn et al., 2018,2019;Howland et al., 2020;Noraña-Zhou et
al., 2020). Patterns of sensory signals are known to shape the de-
velopment of neural circuits involved in sensory systems, and we
show that circuits involved in cognitive functions also may be
affected. Further, almost all previous studies have quantified the
integrity of the uncinate fasciculus using tensor-based measures
such as fractional anisotropy, and axial and radial diffusivity.
These measures rely on the tensor model, which assumes a single
fiber orientation per voxel and does not properly account for
fiber crossing, bending, or twisting (Alexander et al., 2001). A
strength of our approach of modeling multiple fiber orientations
using orientation distribution functions is possibly more likely to
approximate microstructural properties of complex neural tissue
than the tensor model (Gorczewski et al., 2009;Fritzsche et al.,
2010;Yamada et al., 2018).
Anatomically, the uncinate fasciculus is a U-shaped, fanning
white matter bundle with complex structure (Ebeling and von
Cramon, 1992;Bhatia et al., 2012,2017,2018;Riva-Posse et al.,
2014;Vergani et al., 2016) and a number of termination points
in the medial temporal lobes (Ebeling and von Cramon, 1992;
Thiebaut de Schotten et al., 2012; Von Der Heide et al., 2013). It
has only recently been visualized using Q-space imaging meth-
ods that model the U-shaped uncus and orbitofrontal cortex
branching and turning patterns (Leng et al., 2016;Bhatia et al.,
2017). Developmental studies have shown that white matter rap-
idly develops during early infancy, with MTL–PFC pathways like
the uncinate (as well as cingulum) continuing to develop until
the age of 35 years (Hermoye et al., 2006;Asato et al., 2010;Von
Der Heide et al., 2013;Simmonds et al., 2014;Olson et al., 2015).
In animal models, a very similar pattern exists as the amygdala–
prefrontal connection is relatively slow to develop and continues
into adolescence with very rapid growth during the first 10
postnatal days of life followed by synaptic pruning in adolescence
(Cunningham et al., 2002;Johnson et al., 2016). Although histo-
logic evidence is needed to truly determine the significance of
age-related increased anisotropy across maturation, evidence
points to very rapid limbic white matter change in the first 2
years of life, possibly indicating a period of sensitivity in which
environmental stimuli could more drastically affect the develop-
ment of limbic white matter (Yu et al., 2020). In contrast to the
association with the uncinate fasciculus, early life exposure to
unpredictability was not related to integrity in the cingulum bun-
dle, which is in contrast with previous reports suggesting that
this pathway is vulnerable to early life adversity (Choi et al.,
2009;Huang et al., 2012;El Marroun et al., 2018).
The function of the uncinate fasciculus is still not well under-
stood, although recent studies have suggested that it plays a role in
episodic memory, and in particular the adjudication among similar
mnemonic representations during retrieval (Von Der Heide et al.,
2013;Alm et al., 2016). It is well established that episodic memory
involves the MTL, the PFC, as well as their interactions (Jones and
Wilson, 2005;Van Kesteren et al., 2010;Preston and Eichenbaum,
2013;Brincat and Miller, 2015;Eichenbaum, 2017). Further, the
ability to adjudicate among competing memory representations is
thought to rely on hippocampal pattern separation. With this in
mind, our primary behavioral outcome measure (LDI) was based
on the mnemonic similarity task, which is designed to assess hip-
pocampal pattern separation. Our results provide evidence that an
imbalanced ratio of uncinate connectivity to cingulum connectivity
is related to impaired performance on the mnemonic similarity
task. Additionally, our mediation analyses suggest that this imbal-
anced connectivity, a possible indicator of imbalanced maturation,
is a putative mechanism that links the experience of unpredictable
maternal sensory signals early in infancy to impaired memory
function in childhood.
The ratio of integrity parameters of the uncinate fasciculus to
cingulum was a mediator in the association between unpredict-
able maternal sensory signals and performance in our task. This
should not be surprising, as both of these projections comprise
components of the corticolimbic brain circuitry, which is critical
for executing complex behaviors such as memory. Notably, the
overall function of the circuit can be thought of as the combina-
torial sum of the function and connectivity of its distinct compo-
nents (Redish and Gordon, 2017). Thus, whereas augmented
maturation of a single component or a deficit in another in and
by itself may not suffice to distort circuit function, their com-
bined existence may be synergistic, leading to unbalanced func-
tional output.
In conclusion, our findings demonstrate that infant exposure
to unpredictable patterns of maternal care is associated with
imbalanced maturation of the uncinate fasciculus and the cingu-
lum detected during childhood, and that this imbalance may be
associated with deficits in memory function. This is consistent
with our prior work in rodents showing that early life unpredict-
ability leads to increased structural connectivity of the amygdala
to prefrontal cortex pathway in rats (Bolton et al., 2018)andto
deficits in hippocampal memory (Moletetal.,2016b). This
study, along with future investigations, will yield novel insight
into neurobiological mechanisms of vulnerability to cognitive
deficits as a result of unpredictable early environments.
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