Adolescents with prenatal cocaine exposure show subtle alterations in striatal surface morphology and frontal cortical v...

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Title:
Adolescents with prenatal cocaine exposure show subtle alterations in striatal surface morphology and frontal cortical volumes
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Language:
English
Creator:
Roussotte, Florence; Soderberg, Lindsay; Warner, Tamara; Narr, Katherine; Lebel, Catherine; Behnke, Marylou; Davis-Eyler, Fonda and Sowell, Elizabeth
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Notes

Abstract:
Background: Published structural neuroimaging studies of prenatal cocaine exposure (PCE) in humans have yielded somewhat inconsistent results, with several studies reporting no significant differences in brain structure between exposed subjects and controls. Here, we sought to clarify some of these discrepancies by applying methodologies that allow for the detection of subtle alterations in brain structure. Methods: We applied surface-based anatomical modeling methods to magnetic resonance imaging (MRI) data to examine regional changes in the shape and volume of the caudate and putamen in adolescents with prenatal cocaine exposure (n = 40, including 28 exposed participants and 12 unexposed controls, age range 14 to 16 years). We also sought to determine whether changes in regional brain volumes in frontal and subcortical regions occurred in adolescents with PCE compared to control participants. Results: The overall volumes of the caudate and putamen did not significantly differ between PCE participants and controls. However, we found significant (P <0.05, uncorrected) effects of levels of prenatal exposure to cocaine on regional patterns of striatal morphology. Higher levels of prenatal cocaine exposure were associated with expansion of certain striatal subregions and with contraction in others. Volumetric analyses revealed no significant changes in the volume of any subcortical region of interest, but there were subtle group differences in the volumes of some frontal cortical regions, in particular reduced volumes of caudal middle frontal cortices and left lateral orbitofrontal cortex in exposed participants compared to controls. Conclusions: Prenatal cocaine exposure may lead to subtle and regionally specific patterns of regional dysmorphology in the striatum and volumetric changes in the frontal lobes. The localized and bidirectional nature of effects may explain in part the contradictions in the existing literature. Keywords: Prenatal drug exposure, Cocaine, Striatum, Frontal lobes
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doi:10.1186/1866-1955-4-22 Cite this article as: Roussotte et al.: Adolescents with prenatal cocaine exposure show subtle alterations in striatal surface morphology and frontal cortical volumes. Journal of Neurodevelopmental Disorders 2012 4:22. Pgs.1-10
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Roussotte et al. Journal of Neurodevelopmental Disorders 2012, 4:22
http://www.jneurodevdisorders.com/content/4/1/22







Adolescents with prenatal cocaine exposure show

subtle alterations in striatal surface morphology

and frontal cortical volumes

Florence Roussottel'2, Lindsay Soderberg2, Tamara Warner3, Katherine Narr4, Catherine Lebell'2, Marylou Behnke3,
Fonda Davis-Eyler3 and Elizabeth Sowell'2*


Abstract
Background: Published structural neuroimaging studies of prenatal cocaine exposure (PCE) in humans have
yielded somewhat inconsistent results, with several studies reporting no significant differences in brain structure
between exposed subjects and controls. Here, we sought to clarify some of these discrepancies by applying
methodologies that allow for the detection of subtle alterations in brain structure.
Methods: We applied surface-based anatomical modeling methods to magnetic resonance imaging (MRI) data to
examine regional changes in the shape and volume of the caudate and putamen in adolescents with prenatal
cocaine exposure (n =40, including 28 exposed participants and 12 unexposed controls, age range 14 to 16 years).
We also sought to determine whether changes in regional brain volumes in frontal and subcortical regions
occurred in adolescents with PCE compared to control participants.
Results: The overall volumes of the caudate and putamen did not significantly differ between PCE participants and
controls. However, we found significant (P <0.05, uncorrected) effects of levels of prenatal exposure to cocaine on
regional patterns of striatal morphology. Higher levels of prenatal cocaine exposure were associated with expansion
of certain striatal subregions and with contraction in others. Volumetric analyses revealed no significant changes in
the volume of any subcortical region of interest, but there were subtle group differences in the volumes of some
frontal cortical regions, in particular reduced volumes of caudal middle frontal cortices and left lateral orbitofrontal
cortex in exposed participants compared to controls.
Conclusions: Prenatal cocaine exposure may lead to subtle and regionally specific patterns of regional
dysmorphology in the striatum and volumetric changes in the frontal lobes. The localized and bidirectional nature
of effects may explain in part the contradictions in the existing literature.
Keywords: Prenatal drug exposure, Cocaine, Striatum, Frontal lobes


Background
Cocaine is a central nervous system stimulant that binds
to and blocks the activity of monoamine transporters,
resulting in increased synaptic and extracellular levels of
dopamine, norepinephrine, and serotonin [1]. The ani-
mal literature suggests that prenatal cocaine exposure
(PCE) affects brain development in various ways, in


' Correspondence' esowell@chlauscedu
Department of Neurology, University of California, Los Angeles, CA, USA
2Developmental Cognitive Neuroimaging Laboratory (DCNL), Department of
Pediatrics, University of Southern California, Los Angeles, CA, USA
Full list of author information is available at the end of the article


particular through diverse neurochemical and vasocon-
trictive mechanisms, as well as through epigenetic
changes in placental DNA associated with the disruption
of the hypothalamic-pituitary-adrenal (HPA) axis, result-
ing in lasting emotional and behavioral dysregulation
[2].
The neurobehavioral effects of PCE have also been
documented in humans. In particular, children exposed
to cocaine in utero exhibit more negative behavioral
functioning [3,4] than unexposed controls, and experi-
ence difficulties with emotion regulation [5,6]. They
make more errors during attention and response


2012 Roussotte et al., licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
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Roussotte et al Journal of Neurodevelopmental Disorders 2012, 4:22
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inhibition tasks than non-exposed controls [7,8]. They
also show deficits in procedural learning, visual motor,
and motor skills [9,10]. Less is known about the neuro-
behavioral phenotype of adolescents with prenatal co-
caine exposure, though one study suggests impairments
in incidental memory [11].
The functional magnetic resonance imaging (fMRI) lit-
erature of PCE in humans, though small, suggests the
existence of various types of functional brain abnormal-
ities in youth with prenatal exposure to cocaine. For ex-
ample, an earlier perfusion fMRI study reported changes
in global cerebral blood flow (CBF) in the PCE group
compared to controls [12]. While one blood oxygen
level-dependent (BOLD) fMRI study found only trend-
level differences in functional brain activation during a
non-spatial working-memory task between PCE partici-
pants and controls [13], two other BOLD fMRI investi-
gations reported significant ciT :. .. between groups.
.-i. ':1. one study found ,., II in task-
related activation during a response inhibition task [14],
and another reported differences in activation patterns
associated with emotion-memory interactions [5]. Fi-
nally, three recent studies found group differences in
functional and/or effective connectivity between partici-
pants with PCE and controls [15-17].
The neuroimaging literature addressing the structural
effects of prenatal cocaine exposure on human brain de-
velopment has yielded more inconsistent findings. A dif-
fusion tensor imaging (DTI) study found higher average
i: i1'. .' coefficients in the PCE group in left frontal cal-
losal and right frontal projection fibers, suggesting sub-
optimal white matter development in these regions,
. .11i. of prenatal exposure to other drugs of abuse
[18]. Another investigation reported white matter reduc-
tions in the volume of the corpus callosum and gray
matter reductions in occipital and parietal lobes, in PCE
participants compared to controls [19]. The amount of
cocaine ingested by the mother during pregnancy pre-
i,. .. i the area of the corpus callosum and remained sig-
nificant after controlling for prenatal exposure to other
drugs [19]. Two additional studies reported changes in
subcortical structures, p it. ill; decreased caudate
volumes [12,20], and increased gray matter volumes in
the amygdala [12] in youth with prenatal exposure to co-
caine, though these studies did not control for other ges-
tational drug exposures.
In contrast, there are several reports of negative find-
ings with regards to structural brain .i:tt: -........ in PCE.
One study combining structural magnetic resonance im-
aging (sMRI) and magnetic resonance spectroscopy
SilI -., found no structural or volumetric abnormalities
in any brain region in the PCE group [21]. The authors
did observe an increase in frontal white matter creatine
levels in the exposed group compared to controls, but


Page 2 of 10


did not control for prenatal exposure to tobacco or alco-
hol [21]. Another whole-brain volumetric study found
no significant structural differences between PCE parti-
cipants and controls after ,c.il,.l;,i:: for exposure to
other drugs of abuse, suggesting that none of the initially
observed brain volume reductions in the exposed group
could be ii' c li,...I to the specific teratogenic effects of
cocaine [22]. In addition, a recent DTI study which
included prenatal tobacco exposure as a nuisance covari-
ate reported no : i...i .... differences between adoles-
cents with PCE and control participants in any
subregion of the corpus callosum [23].
To help clarify these discrepancies in the structural
neuroimaging literature, here, we investigated the neuro-
logical consequences of prenatal exposure to cocaine
using methodologies that allow for the detection of more
subtle alterations in brain structure. We applied
advanced surface-based anatomical modeling methods
to MRI data, in order to examine regional changes in
the shape and volume of the caudate and putamen. In
addition, we examined regional volumetric differences
between participants with prenatal cocaine exposure and
unexposed controls in several subcortical and frontal
cortical regions of interest implicated by some, though
not all prior studies as indicated above.
Because of the mechanisms of action of cocaine, we
focused our surface-based analyses on dopamine-rich
striatal regions. Although cocaine is less neurotoxic than
other stimulant drugs of abuse (such as methampheta-
mine) and may act as an intrauterine stressor rather
than as a direct toxin [2], animal models have shown
that prenatal exposure to cocaine leads to changes in
dopamine receptor activity and subcellular i i.,..
-' i]. and alterations in dendritic spine density in striatal
medium spiny neurons [25]. Thus, in this study, we
hypothesized that prenatal cocaine exposure would be
associated with subtle structural .I': ... -.. in the
morphology of the caudate and putamen. .-... i'.' il;
we i ... i. .. Ia ... .' correlation between levels of pre-
natal cocaine exposure and extent of structural abnor-
malities in striatal surface ",," I 1,,.!.-_
In adolescents with prenatal cocaine exposure, we also
hypothesized relationships between performance on
neuropsychological tests and regional changes in striatal
surface morphology. In particular, we expected that
deformations in the dorsal caudate (part of the executive
loop [26]) would correlate with decreased scores on tests
of executive functioning (Stroop test, Trail Making test
part B), whereas deformations in the putamen (part of
the fronto-striatal motor loop [26]) would correlate with
lower scores on a visuomotor task (Trail Making test
part A).
We also investigated possible regional volumetric dif-
ferences between groups in subcortical and frontal






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cortical regions. We chose to restrict our analyses to
these particular regions of interest because previous neu-
roimaging studies of structural and/or metabolic brain
abnormalities in humans with prenatal cocaine exposure
suggested evidence for differences in these areas. That
is, most of the published structural human studies with
significant results reported group differences in frontal
[18,21] or subcortical [12,20] structures. Thus, in this
study, we expected that prenatal cocaine exposure would
be associated with subtle volumetric differences in
frontal and subcortical areas.

Methods
Participants
Forty volunteers, age range 14 to 16 years, including 28
adolescents with prenatal cocaine exposure and 12 unex-
posed controls were studied with structural MRI col-
lected at the University of Florida. Study approval was
granted by the University of Florida Institutional Review
Board, and a federal Certificate of ( ....,.i. ni, .1i; pro-
tects the confidentiality of the data. All participants were
the offspring of women ... ,i' i;, 1. enrolled during
pregnancy in a L ... ,I.sI.' ii cohort study of the develop-
mental effects of prenatal cocaine exposure [27]. A sep-
arate informed consent from the child's primary
caregiver and assent by the child were obtained before
the current study. D t1I. .1 drug histories covering the
period from 3 months prior to gestation through birth
were obtained for all mothers. Prenatal cocaine exposure
was measured as the ratio of weeks of maternal cocaine
use during pregnancy over weeks of gestation. The ex-
tent of PCE in exposed participants ranged from 0.04 to
1, with a mean ratio of 0.402 and a standard deviation of
0.25 (Table 1).
In i. i::..:! to neuroiraging data, biologic assays were
available for participants (hair samples, tested for co-
caine at ages 10.5 years and 12.5 years), as %.. I: as neuro-
psychological data. Participants were administered a
battery of tests at the time of scanning, which included a
word-color interference Stroop test and a Trail Making
test. We chose to examine these two particular measures
of neurocognitive function in order to investigate rela-
tionships between the morphology of striatal structures
in the executive and motor loops and tests of response
inhibition i '. i ': test), task switching (Trail Making test
part B) and visuomotor function (Trail Making test part
A).

Image acquisition
Neuroimaging data were collected on a Philips 3 T
Achieva MRI scanner. Conventional MRI sequences
(axial T2 multishot turbo field echo) were obtained to
detect possible I ... "i ."... pathology. Volumetric T1-
weighted image acquisition used a multishot gradient


Page 3 of 10


spin echo pulse sequence with 8.1-ms TR, 3.7-ms TE,
240 x 240 x 234 matrix, 1 mm isotropic voxel size, and
an acquisition time of 10 min, 14 s.

Image preprocessing and processing
Surface-based analyses
For the surface-based analyses, each brain volume
was corrected for radiofrequency field inhomogeneities
[28] and placed into the standard coordinate system
of the ICBM-305 average brain volume using a three-
translation and three-rotation rigid-body transformation
[29]. This procedure corrects for i I. i. .i. in head
alignment between subjects to ensure that region of
interest measurements are not ,:: '' ,: ,,. .i by different
brain orientations between subjects [29].
The methods for surfaced-based image analysis have
been described in detail elsewhere [30-32]. Briefly, two
investigators blind to exposure status (FFR and LS)
devised a i. -:1 .1 manual tracing protocol for the caud-
ate and putamen, which included directions about the
order and direction of tracing, numerous visual aids to
facilitate the .. -, uIi, '('.1 of anatomical landmarks, and
precise instructions for dealing with scan artifacts. Stri-
atal contours were then manually outlined by the same
two : .- t;.- :ii --. on contiguous coronal slices for every
subject (Figure 1). High intra-rater and inter-rater reli-
abilities (intraclass correlations >0.95) were established
based on independent blinded measurement of six scans
used in this study. Subsequently, manually derived con-
tours were transformed into 3D parametric surface mesh
models with normalized spatial frequency of the surface
points within and across brain slices. Each structure was
made into a parametric grid containing 100 x 150 grid
points or surface nodes. This step ensures precise com-
parison of anatomy between subjects at each surface
point of the structure. A 3D medial curve was computed
along the long axis for the surface model of each struc-
ture and radial distance measures (distance from the
medial core to the surface) were estimated and recorded
at each corresponding surface point. These values were
used to generate individual distance maps, which were
combined to produce correlation maps ii' ... for
visualization of the relationships between striatal morph-
ology and (1) levels of prenatal cocaine exposure, and
(2) neuropsychological test scores in exposed partici-
pants. In all analyses, quantitative measures of prenatal
exposure to tobacco, alcohol, and marijuana were
included as nuisance covariates, as well as sex, cube root
of total brain volume, and cocaine use by adolescent par-
ticipants themselves. Since this method estimates radial
distance measures, and i, 111m. from the i .:, ,i core to
the surface is a ID measure, cube root of brain volume
was used in place of total brain volume (a 3D measure),
in order to make the units comparable.







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Table 1 Demographic information and neuropsychological data for subjects by group
Control group Prenatal cocaine exposure group
(CON, n= 12) (PCE, n=28)
Age (in whole years) 14.7 0.49 14.80.72


Gender


Cocaine exposure (weeks of maternal cocaine use divided by weeks
gestation)


Tobacco exposure (average number


garettes per day)


Alcohol exposure (average ounces per day)
Marijuana exposure (average number of joints per day,
Postnatal cocaine exposure (hair sample positive for cc
10.5 years and/or 12.5 years)
Total brain volume (in mm3)


Word-color interference Stroop test, raw score
Trail Making test, part A completion time (in seconds)
Trail Making test, part B completion time (in seconds)
Mean values are given with standard deviation.
aSignificant differences between groups (P <0.05).
bTrend-level differences between groups (0.05

0.020 0.00
0.007 0.0


0.003 0.010
caine at age 6 yes / 6 no

1,582,350
188,214
44417 9.54
11.750 4.37
23.000 7.86


Volumetric analyses
Preprocessing and definition of cortical and subcortical
gray matter regions on structural images were conducted
in the UCLA Laboratory of Neuro Imaging (LONI) Pipe-
line Processing Environment [33-35] and using FreeSur-
fer's automated brain segmentation software (FreeSurfer


Figure 1 Region of interest delineation. The left and right
caudate and putamen were manually delineated on contiguous
coronal slices following a detailed protocol devised by the
investigators


4.0.5, http://surfer.nmr.mgh.harvard.edu), as described in
the work of Fischl and Dale [36-38]. We obtained vol-
ume measurements of seven subcortical brain regions
(thalamus, caudate, putamen, pallidum, hippocampus,
amygdala, and ventral diencephalon) as well as six
frontal cortical regions (caudal middle frontal cortex,
rostral middle frontal cortex, lateral orbitofrontal cortex,
medial orbitofrontal cortex, superior frontal cortex, and
frontal poles). During preprocessing, high-resolution T1-
weighted image acquisitions for each participant were
visually inspected for motion artifacts by a trained rater
based on a 5-point Likert scale illustrating the severity
of motion effects. No participants were rejected due to
motion artifacts; however, one subject was rejected due
to poor gray -white matter contrast, and another subject
was rejected because the raw image data files appeared
corrupted. In all remaining participants (n = 40), the T1-
weighted images were brain extracted, and gray-white
matter boundaries were automatically delineated. All
brain extractions were inspected visually and corrected
manually as needed.
Volumes for the seven subcortical and six frontal cor-
tical regions of interest, as well as total intracranial
volumes were calculated using FreeSurfer's automatic
quantification of cortical and subcortical structures. Pro-
cedures are described in detail elsewhere [38]. In sum-
mary, a neuroanatomical label was assigned to each
voxel in an individual's structural MRI based on prob-
abilistic information estimated from a manually labeled
training set. This manually labeled training set is a result
of validated methods from the Center of Morphometric


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Group
differences
P0.439
P=0.039a


P <0.001

P <0.001
P-0.011O
P 0.091b
P 0.030'


18 girls/
10 boys
0.402 0.25

8.155 7.79
0.199 0.371
0.125 0.367
10 yes / 18 no

1,559,794
177,613
39.857 9.15
12.786 +4.78
29.643 11.00


P 0.846


P 0.605
P 0.882
P 0.360






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Analysis (http://www.cma.mgh.harvard.edu). To disam-
biguate the overlap in intensities between different
anatomical structures, FreeSurfer utilized spatial infor-
mation. Two transformations were performed. First,
an optimal linear transformation was carried out by
maximizing the likelihood of the native image given a
manually labeled atlas. Second, a non-linear transform-
ation was executed on the output of the prior registra-
tion step. Finally, a Bayesian parcellation was conducted
by using prior spatial information [39,40]. At the end of
this processing stream, three probabilities were calcu-
lated for each voxel: (1) the probability of the voxel
belonging to each of the label classes, based on its loca-
tion, (2) the neighborhood function, used to determine
the :ii. IhI .... that the voxels belong to a class, based on
the classification of neighboring voxels, and (3) the re-
sult of the probability distribution function for each
voxel based on its intensity.
The accuracy of this technique was shown to be simi-
lar to manual methods. The automated segmentations
have been found to be statistically ,.I;. I:,L,: li :1.1 from
manual labeling [38]. Being completely automated, Free-
surfer volume estimates are highly reliable. Nonetheless,
in the current study, each brain image was visually
inspected for validity of all regions by a single trained
blind rater. In over one-third of subjects, the segmenta-
tions of the caudate and putamen were judged unsatis-
factory, due to pulsation artifacts around the striatum on
the high-resolution T1-weighted images. Therefore, the
volumes of the caudate and putamen were calculated
from the ii ...r ll derived contours (obtained in the
surface-based analyses) for all subjects (n=40), and
these values were used in place of the FreeSurfer outputs
in all statistical analyses.

Statistical analyses of demographic, neuropsychological,
and volumetric data
Statistical analyses were conducted using SYSTAT 12.0
and SPSS 20.0. Group i.11. i i i. in age, total brain vol-
ume, neuropsychological test performance, and prenatal
exposure to tobacco, alcohol, and marijuana were evalu-
ated using two-sample independent t-tests. Group differ-
ences in gender and postnatal cocaine exposure were
assessed with a Pearson Chi-Square Test.
In volumetric analyses, L .i. i' l .I in regional
brain volumes were evaluated using separate one-way
ANOVA tests for each individual region of interest. In
all analyses, prenatal exposure to cocaine was modeled
as the independent variable, while the volume (in mm3)
of the region of interest was used as the dependent vari-
able. All analyses included the following covariates: pre-
natal exposure to alcohol, tobacco, and marijuana, in
addition to sex, total brain volume, and cocaine use by
participants themselves (as measured by a positive hair


Page 5 of 10


sample at 10.5 and/or 12.5 years of age). Two-way ANO-
VAS were subsequently performed in order to examine
1.., i.i. interactions between pre- and postnatal cocaine
exposure.
Associations between neuropsychological test scores
and levels of prenatal cocaine exposure were investigated
with multiple regression analyses using the following
equation: Performance = Constant + Level of Prenatal Cocaine
Exposure + Prenatal Alcohol Exposure + Prenatal Tobacco
Exposure + Prenatal Marijuana Exposure + Sex + Cocaine Use
by Participants (as measured by a positive hair sample at 10.5
and/or 12.5 years of age).

Results
Demographics
Demographic descriptors are reported in Table 1. The
PCE and CON groups did not differ from each other in
age (P=0.439) but showed a :..,, difference in
gender i, I,!:.I..i.. (P=0.039), with the exposed .....
comprising more girls. The two groups ..-: :i- .i -i. dif-
fered from each other in prenatal exposure to tobacco
(P <0.001) and alcohol (P=(,,: I'1. with the PCE ...
showing ;. miil;.. i' higher levels of exposure to these
drugs than participants in the CON group. We also
reported a trend-level difference in prenatal exposure to
marijuana (P= 0.091) and a significant '.IT ..i .. in post-
natal exposure to cocaine (P=0.030) assessed by
cocaine-positive hair samples at age 10.5 years and/or
12.5 years. The PCE .i. ,:i tended to have higher levels
of prenatal marijuana exposure, and while the CON
group comprised an equal number of participants with
and without postnatal cocaine exposure, the PCE group
included almost twice as many non-users as users. The
two groups did not ,i:ll, in total brain volume
(P= 0.846). Nevertheless, in all analyses presented below,
total brain volume was used as a covariate along with
sex, postnatal cocaine exposure, and prenatal exposure
to other drugs of abuse in order to eliminate any vari-
ance due to possible disparities in overall brain volume
within groups.

Surface-deformation analyses
Main effects of prenatal cocaine exposure
The .... '. :!! volumes of the caudate and putamen did not
significantly i-11'. between participants with prenatal co-
caine exposure (the PCE group) and controls (the CON
group). In addition, i-ll i-. ..i in caudate and putamen
morphology between these two groups were non-
significant after regressing out prenatal exposure to
other drugs of abuse, total brain volume, sex, and co-
caine use, even when prenatal tobacco exposure was not
included as a nuisance covariate. However, 3D surface
statistics revealed ..^i :.. (P <0.05, uncorrected)
effects of the amount of prenatal exposure to cocaine






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on regional patterns of striatal morphology across all
participants.
Higher levels of prenatal cocaine exposure were asso-
ciated with contraction of striatal surfaces in the ventro-
medial and in the dorsal caudate, and some regions of
expansion in the ventrolateral caudate. These effects
were stronger in the left caudate (F.. ni.. 2.2 and 2.3).
Similar but less pronounced results were observed in the
right caudate (data not shown).
Greater prenatal cocaine exposure was associated with
contraction of striatal surfaces in the posterior putamen
and in the ventrolateral and dorsomedial putamen.
Higher levels of prenatal cocaine exposure were asso-
ciated with large areas of expansion in the anterior puta-
men, as well as in the dorsolateral and ventromedial
putamen. These effects were stronger in the right puta-
men (Figures 2.4 and 2.5). Similar but less pronounced
results were observed in the left putamen (data not
shown). Comparable correlational maps in terms of
strength and extent were obtained in the left and right
caudate and putamen when prenatal tobacco exposure
was not included as a nuisance covariate (data not
shown). These results did not remain significant after
correcting for multiple spatially correlated comparisons
using permutation testing.

Neuropsychological correlates of striatal morphology
Following these initial analyses, we examined the two
ROIs that showed the most significant effects (left caud-
ate and right putamen), and ;.... i:. ,i. 11 relationships
between neuropsychological test scores and regional
deformations of the striatal surface in exposed subjects.
: ... :.. we first examined correlations between mea-
sures of executive functioning and regional deformation
of the left caudate surface. Higher scores (better per-
formance) on the Stroop test (Figure 2.6) were asso-
ciated with larger volume in -1., _:..'.. of the dorsal
caudate, while longer response times (lower perform-
ance) on part B of the Trail Making test (Figure 2.7) cor-
related with larger volume in other parts of the dorsal
caudate.
We also investigated correlations between a measure
of visuomotor functioning and regional deformation of
the right putamen surface. Longer response times on
part A of the Trail Making test were associated with lar-
ger volume of the medial putamen, mostly in the poster-
ior region (Figure 2.8). None of these results remained
significant after performing permutation testing in order
to correct for multiple spatially correlated comparisons.

Volumetric analyses
In these analyses, we examined group .:irr...,.. in re-
gional brain volumes between the PCE ._. ,,' and the
CON group. As in the surface-deformation analyses, in


Page 6 of 10


addition to sex, total brain volume, and cocaine use by
the participants themselves, we also used prenatal expos-
ure to alcohol, tobacco, and 11 i ,',. ll i as nuisance cov-
ariates in all analyses in an attempt to detect the specific
effects of prenatal cocaine exposure.
Consistent with the surface-based analyses in which
we found no significant group differences in overall
volumes of the caudate and putamen based on
:!~~:~! ;!! -.--i..ed contour, here we observed no signifi-
cant changes in the volume of any subcortical region of
interest in the PCE group compared to the CON group
in analyses based on automated segmentation. However,
we detected group differences in the volumes of some
frontal cortical regions.
We observed .. iii.. if (uncorrected) reductions in
regional volumes in the left (P= 0.046) and right
(P= 0.036) caudal middle frontal cortices, and in the left
lateral orbitofrontal cortex (P= 0.048), in participants
with prenatal cocaine exposure compared to controls
(Figure 3). On the other hand, in the left (P= 0.072) and
right (P= 0.098) frontal poles, we observed trend-level
increases in regional brain volumes in the PCE i
compared to controls (F: .. ... 3).
We found no significant main effects of postnatal co-
caine exposure (cocaine use by participants) on the vol-
ume of any frontal cortical region, and there were no
significant interactions between pre- and postnatal co-
caine exposure. Moreover, neuropsychological perform-
ance on the word-color interference Stroop Test, and on
parts A and B of the Trail Making Test did not Ih;lu,
significantly between the PCE and control -....=.
(Table 1); and there were no significant correlations
between levels of prenatal cocaine exposure and neuro-
psychological test scores, after co-varying for prenatal
exposure to other drugs of abuse, sex, and postnatal co-
caine exposure.

Discussion and conclusions
Taken together, these results suggest that prenatal co-
caine exposure may lead to :-...:.!!i specific patterns
of morphological changes in the striatum and subtle
volumetric ,I1li i. ..., ..in certain frontal cortical regions.
The most .. ii:. nlt :!!.in,!! in our analyses of caudate
morphology was an association between levels of pre-
natal cocaine exposure and surface contraction in the
ventromedial and dorsolateral caudate. The ventro-
medial caudate is part of the lateral orbitofrontal striatal
loop, which is involved in the regulation of emotion and
social behavior [26]. Interestingly, we also reported re-
gional volume changes in the left lateral orbitofrontal
cortex in the PCE group compared to controls. The
dorsolateral caudate, on the other hand, is part of the
executive loop associated with higher-order cognitive
functions [26], and we also found local volumetric







Roussotte et a. Journal of Neurodevelopmental Disorders 2012, 4:22
http://www.jneurodevdisorders.com/content/4/1/22


Left Caudate (Medial) Left Caudate (Lateral)
2 3





II6

6 7


Right Putamen (Lateral) Right Putamen (Medial)
4 5


Figure 2 2, 3, 4, and 5: Uncorrected surface maps depicting relationships between levels of prenatal cocaine exposure and regional
deformations of striatal surface (n=40). Blue-to-light-blue shading indicates regions where higher levels of prenatal cocaine exposure are
associated with contraction of striatal surfaces. Red-to-yellow shading displays regions where higher exposure levels are associated with
expansion of the surfaces. For all statistical maps, the color bar encodes the uncorrected P values (P <0.05) for the observed effects. 6, 7, 8:
Uncorrected surface maps depicting relationships between neuropsychological scores (6: Stroop, 7: Trails A, 8: Trails B) and regional
deformations of striatal surface in exposed subjects (n =28). Red-to-yellow shading displays regions where higher scores (better performance
on the Stroop test but longer response times on the Trails test) are correlated with larger regional striatal volumes. Few negative correlations
were observed in these analyses. For all statistical maps, the color bar encodes the uncorrected P values (P <0.05) for the observed effects.


differences in the frontal poles, which play a role in
spatial working memory, response inhibition [41], and
the evaluation of self-generated [42] and goal-directed
[43] decisions. Therefore, the findings presented here
may represent some of the neural correlates of the diffi-
culties in emotional regulation [5,6] and impairments in
attention, response inhibition [7], and visuospatial work-
ing memory [44] that have been reported in children
with prenatal cocaine exposure.
The putamen is part of the fronto-striatal loop
involved in motor control [26]. Most premotor area pro-
jections are directed to the medial putamen, and most
supplementary motor area projections terminate in the
posterior putamen [45], and in both subregions we
found that greater prenatal cocaine exposure was asso-
ciated with a contraction of striatal surfaces. In addition,
we observed significant reductions in regional volumes
in the bilateral caudal middle frontal cortices in the PCE
group compared to controls, and the caudal part of the
middle frontal gyrus corresponds to premotor brain
areas. Therefore, it is possible that these findings may be
related to the deficits in fine motor coordination that
have been reported in this population [10].
While the direction of changes in striatal surface struc-
ture were not predicted a priori, it should be noted that
prenatal cocaine exposure was associated with surface
contraction in some subregions, and expansion in
others. Though the biological mechanisms contributing
to these findings remain unclear, the bidirectional nature


of regional effects may explain why overall differences in
striatal volume were not detected in this study between
exposed and control participants in either the surface-


Page 7 of 10






Roussotte et al. Journal of Neurodevelopmental Disorders 2012, 4:22
http://v .-., ...i- ... -, .. .,- 1/22



based or the volumetric analyses. Similarly, while we did
not have .1- :'" predictions about the direction of
changes in regional frontal cortical volumes, prenatal co-
caine exposure was shown to be associated with volume
reductions in some frontal subregions, and increased
volumes in others. The reasons for this discrepancy re-
main unclear, but the localized and bidirectional nature
of frontal cortical effects may explain in part why certain
neuroimaging studies found significant structural differ-
ences in the frontal lobes, while others reported negative
results.
Consistent with our predictions, we observed very nar-
rowly localized correlations between measures of execu-
tive functioning and regional deformation of the dorsal
caudate surface. However, the specific areas where this
association was -.!,-ir.. ., did not correspond exactly to
the subregions of the dorsal caudate where higher levels
of prenatal exposure were correlated with greater dys-
morphology. The specific areas of the dorsal caudate
showing correlations with measures of executive func-
tioning also differed by task: they were more superior
and medial for the Stroop test than for part A of the
Trail Making test.
As predicted, we also observed a :,,!:.i,;':.; .,,,.. .. ,
correlation between a measure of visuomotor performance
and regional deformation of the putamen surface, which
was m. !!.I. :!!, in the medial and posterior putamen, where
most premotor and supplementary motor area projections
terminate [45], ,,-_ _. ..-2 a possible association between
neurological and behavioral abnormalities.
However, while these results suggest that prenatal
exposure to cocaine may affect the morphology of the
striatum and regional frontal lobe volumes, it is import-
ant to keep in mind that the effect sizes were small for
all of the results reported here, and that the surface-
deformation and volumetric maps were not corrected
for multiple spatially correlated comparisons. Neverthe-
less, the fact that we reported subtle changes consistent
with :.,.i., from the animal literature and with our
a-priori hypotheses, suggests that these differences may
be due in part to the specific effects of prenatal cocaine
exposure.
We found no association between PCE and neuro-
logical test scores, which suggests that brain structure
may be a more sensitive biomarker to levels of prenatal
cocaine exposure than neuropsychological test perform-
ance. This is consistent with :.!!,:ii.. from the animal
literature, -*.--..- .- that cognitive tests may be more
sensitive to the pattern of maternal consumption than to
the amount of cocaine intake, even in the presence of
neurobiological alterations [46]. Despite showing evi-
dence for abnormal neuronal migration and cortical
lamination as well as neurochemical differences, rhesus
monkeys with both I'.- doses' and 'low doses' of PCE


Page 8 of 10


do not significantly differ from controls in ...-! (, .- per-
formance, whereas monkeys in the 'escalating dose'
group show impairments [46].
It should be noted that we did not have data about
participants' use of other drugs, thus we cannot exclude
the *..... i.:ir that postnatal exposure to other sub-
stances of abuse may have affected the findings. Another
important limitation is that neuroimaging data was avail-
able for only 12 adolescent controls. Though we cannot
rule out the eventuality that a larger control group
would have allowed for the detection of slightly more
robust group il ::: .1. .. in the context of the existing
literature, these findings support the notion that the
effects of PCE on brain structure may be quite subtle.
An alternative explanation to findings of modest effects
in the current study may be that the : -, .- .i1 il .;,1 .1,,
cant alterations observed simply reflect relatively minor
consequences of PCE on brain development. Some pub-
lications suggested that cocaine may be a relatively weak
teratogen with few observable neurological or behavioral
consequences in humans [47], unlike other common
substances of abuse during pregnancy, which have been
more convincingly linked to psychopathology risk, such
as alcohol [48] and nicotine [49].
The small effect sizes observed here as well as regional
differences in the direction of effects may help explain
why prior :i. .t;. i;i.., of the consequences of prenatal
cocaine exposure on brain structure have yielded some-
what conflicting results. Although animal studies of
PCE, particularly studies of non-human primates, clearly
demonstrate the potential of prenatal cocaine exposure
to interfere with brain development at a cellular and bio-
chemical level in various brain regions [24,25,47,50-52],
they also -. that the types and severity of PCE
effects largely depend on the route, dose, gestational
period, and pattern of consumption [46]. These could be
additional .... ., :i'.,- factors to the .* :..... in
the existing human neuroimaging literature, and to the
small effect sizes reported here.
Thus, it is important that future neuroimaging studies
of prenatal cocaine exposure with larger samples collect
information about adolescent participants' use of other
substances, specific patterns and timing of maternal co-
caine consumption, and aim to integrate observations
from different brain imaging modalities. This will help
determine how structural, metabolic, and functional
brain abnormalities resulting from PCE relate to real-
life difficulties these children face outside the scanner,
as subtle neurological changes may very well be asso-
ciated with important behavioral, cognitive, or emotional
impairments.
Although several promising psychosocial prevention
strategies for pregnant women addicted to cocaine have
been identified '-.1. effective remediation i. ;, and








Roussotte et al Journal of Neurodevelopmental Disorders 2012, 4:22
http://v .., ....- .... .. ... -. l 1/22





treatments for prenatally exposed children remain to be
developed. The improvement of such strategies will re-
quire that we gain a better understanding of the :.. -,
localized and perhaps subtle neurological abnormalities
resulting from prenatal cocaine exposure in order to
facilitate the translation of research findings to clinical
practice.

Competing interests
The authors declare that they have no competing interests

Authors' contributions
FR analyzed and interpreted the data and was the main writer of the
mranuscrit LS helped with data otocessing and analysis TW helped with
data collect-on and data interpretation KN helped with technical aspects of
data analysis and data interpretation CL helped with data interpretation and
helped revise the manuscript MB helped with data collection and
interpretation r:DE helped with data coi:ection and interpretation ERS was
the principal investigator, who supervised the whole project, and helped
write the manuscript Al authors read and approved the nal manuscript

Acknowledgments
This work was supported by National Inst tute of Drug Abuse Grants R21
DA i5878 and R01 DA01731 and the Marc of Dimes (6FY2008 0) awarded
to ERS Additional support was provided by Grants R21 DA027561 awarded
to TW and ERS and R01 DA05854 awarded to FDE and MB

Author details
Department of Neurology, University of California, Los Angeles, CA, USA
2Developmental Cognitive Neuroimaging Laboratory (DCNL), Department of
Pediatrics, University of Southern California, Los Angeles, CA, USA
Department of Pediatrics, University of Florida, Gainesville FL, USA
4Laboratory of Neurolmaging, Department of Neurology, University of
California, Los Angeles, CA, USA

Received: 26 April 2012 Accepted: 19 July 2012
Published: 7 August 2012

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doi:10.1186/1866-1955-4-22
Cite this article as: Roussotte et al Adolescents with prenatal cocaine
exposure show subtle alterations in striatal surface morphology and
frontal cortical volumes. Journal ofNeurodevelopmental Disorders 2012
422


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RESEARCHOpenAccessAdolescentswithprenatalcocaineexposureshow subtlealterationsinstriatalsurfacemorphology andfrontalcorticalvolumesFlorenceRoussotte1,2,LindsaySoderberg2,TamaraWarner3,KatherineNarr4,CatherineLebel1,2,MarylouBehnke3, FondaDavis-Eyler3andElizabethSowell1,2*AbstractBackground: Publishedstructuralneuroimagingstudiesofprenatalcocaineexposure(PCE)inhumanshave yieldedsomewhatinconsistentresults,withseveralstudiesreportingnosignificantdifferencesinbrainstructure betweenexposedsubjectsandcontrols.Here,wesoughttoclarifysomeofthesediscrepanciesbyapplying methodologiesthatallowforthedetectionofsubtlealterationsinbrainstructure. Methods: Weappliedsurface-basedanatomicalmodelingmethodstomagneticresonanceimaging(MRI)datato examineregionalchangesintheshapeandvolumeofthecaudateandputameninadolescentswithprenatal cocaineexposure(n=40,including28exposedparticipantsand12unexposedcontrols,agerange14to16years). Wealsosoughttodeterminewhetherchangesinregionalbrainvolumesinfrontalandsubcorticalregions occurredinadolescentswithPCEcomparedtocontrolparticipants. Results: TheoverallvolumesofthecaudateandputamendidnotsignificantlydifferbetweenPCEparticipantsand controls.However,wefoundsignificant( P <0.05,uncorrected)effectsoflevelsofprenatalexposuretococaineon regionalpatternsofstriatalmorphology.Higherlevelsofprenatalcocaineexposurewereassociatedwithexpansion ofcertainstriatalsubregionsandwithcontractioninothers.Volumetricanalysesrevealednosignificantchangesin thevolumeofanysubcorticalregionofinterest,butthereweresubtlegroupdifferencesinthevolumesofsome frontalcorticalregions,inparticularreducedvolumesofcaudalmiddlefrontalcorticesandleftlateralorbitofrontal cortexinexposedparticipantscomparedtocontrols. Conclusions: Prenatalcocaineexposuremayleadtosubtleandregionallyspecificpatternsofregional dysmorphologyinthestriatumandvolumetricchangesinthefrontallobes.Thelocalizedandbidirectionalnature ofeffectsmayexplaininpartthecontradictionsintheexistingliterature. Keywords: Prenataldrugexposure,Cocaine,Striatum,FrontallobesBackgroundCocaineisacentralnervoussystemstimulantthatbinds toandblockstheactivityofmonoaminetransporters, resultinginincreasedsynapticandextracellularlevelsof dopamine,norepinephrine,andserotonin[1].Theanimalliteraturesuggeststhatprenatalcocaineexposure (PCE)affectsbraindevelopmentinvariousways,in particularthroughdiverseneurochemicalandvasocontrictivemechanisms,aswellasthroughepigenetic changesinplacentalDNAassociatedwiththedisruption ofthehypothalamic-pituitary-adrenal(HPA)axis,resultinginlastingemotionalandbehavioraldysregulation [2]. TheneurobehavioraleffectsofPCEhavealsobeen documentedinhumans.Inparticular,childrenexposed tococaine inutero exhibitmorenegativebehavioral functioning[3,4]thanunexposedcontrols,andexperiencedifficultieswithemotionregulation[5,6].They makemoreerrorsduringattentionandresponse *Correspondence: esowell@chla.usc.edu1DepartmentofNeurology,UniversityofCalifornia,LosAngeles,CA,USA2DevelopmentalCognitiveNeuroimagingLaboratory(DCNL),Departmentof Pediatrics,UniversityofSouthernCalifornia,LosAngeles,CA,USA Fulllistofauthorinformationisavailableattheendofthearticle 2012Roussotteetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.Roussotte etal.JournalofNeurodevelopmentalDisorders 2012, 4 :22 http://www.jneurodevdisorders.com/content/4/1/22

PAGE 2

inhibitiontasksthannon-exposedcontrols[7,8].They alsoshowdeficitsinprocedurallearning,visualmotor, andmotorskills[9,10].Lessisknownabouttheneurobehavioralphenotypeofadolescentswithprenatalcocaineexposure,thoughonestudysuggestsimpairments inincidentalmemory[11]. Thefunctionalmagneticresonanceimaging(fMRI)literatureofPCEinhumans,thoughsmall,suggeststhe existenceofvarioustypesoffunctionalbrainabnormalitiesinyouthwithprenatalexposuretococaine.Forexample,anearlierperfusionfMRIstudyreportedchanges inglobalcerebralbloodflow(CBF)inthePCEgroup comparedtocontrols[12].Whileonebloodoxygen level-dependent(BOLD)fMRIstudyfoundonlytrendleveldifferencesinfunctionalbrainactivationduringa non-spatialworking-memorytaskbetweenPCEparticipantsandcontrols[13],twootherBOLDfMRIinvestigationsreportedsignificantdifferencesbetweengroups. Specifically,onestudyfoundgroupdifferencesintaskrelatedactivationduringaresponseinhibitiontask[14], andanotherreporteddifferencesinactivationpatterns associatedwithemotion-memoryinteractions[5].Finally,threerecentstudiesfoundgroupdifferencesin functionaland/oreffectiveconnectivitybetweenparticipantswithPCEandcontrols[15-17]. Theneuroimagingliteratureaddressingthestructural effectsofprenatalcocaineexposureonhumanbraindevelopmenthasyieldedmoreinconsistentfindings.Adiffusiontensorimaging(DTI)studyfoundhigheraverage diffusioncoefficientsinthePCEgroupinleftfrontalcallosalandrightfrontalprojectionfibers,suggestingsuboptimalwhitematterdevelopmentintheseregions, regardlessofprenatalexposuretootherdrugsofabuse [18].Anotherinvestigationreportedwhitematterreductionsinthevolumeofthecorpuscallosumandgray matterreductionsinoccipitalandparietallobes,inPCE participantscomparedtocontrols[19].Theamountof cocaineingestedbythemotherduringpregnancypredictedtheareaofthecorpuscallosumandremainedsignificantaftercontrollingforprenatalexposuretoother drugs[19].Twoadditionalstudiesreportedchangesin subcorticalstructures,specificallydecreasedcaudate volumes[12,20],andincreasedgraymattervolumesin theamygdala[12]inyouthwithprenatalexposuretococaine,thoughthesestudiesdidnotcontrolforothergestationaldrugexposures. Incontrast,thereareseveralreportsofnegativefindingswithregardstostructuralbraindifferencesinPCE. Onestudycombiningstructuralmagneticresonanceimaging(sMRI)andmagneticresonancespectroscopy (MRS)foundnostructuralorvolumetricabnormalities inanybrainregioninthePCEgroup[21].Theauthors didobserveanincreaseinfrontalwhitemattercreatine levelsintheexposedgroupcomparedtocontrols,but didnotcontrolforprenatalexposuretotobaccooralcohol[21].Anotherwhole-brainvolumetricstudyfound nosignificantstructuraldifferencesbetweenPCEparticipantsandcontrolsaftercontrollingforexposureto otherdrugsofabuse,suggestingthatnoneoftheinitially observedbrainvolumereductionsintheexposedgroup couldbeattributedtothespecificteratogeniceffectsof cocaine[22].Inaddition,arecentDTIstudywhich includedprenataltobaccoexposureasanuisancecovariatereportednosignificantdifferencesbetweenadolescentswithPCEandcontrolparticipantsinany subregionofthecorpuscallosum[23]. Tohelpclarifythesediscrepanciesinthestructural neuroimagingliterature,here,weinvestigatedtheneurologicalconsequencesofprenatalexposuretococaine usingmethodologiesthatallowforthedetectionofmore subtlealterationsinbrainstructure.Weapplied advancedsurface-basedanatomicalmodelingmethods toMRIdata,inordertoexamineregionalchangesin theshapeandvolumeofthecaudateandputamen.In addition,weexaminedregionalvolumetricdifferences betweenparticipantswithprenatalcocaineexposureand unexposedcontrolsinseveralsubcorticalandfrontal corticalregionsofinterestimplicatedbysome,though notallpriorstudiesasindicatedabove. Becauseofthemechanismsofactionofcocaine,we focusedoursurface-basedanalysesondopamine-rich striatalregions.Althoughcocaineislessneurotoxicthan otherstimulantdrugsofabuse(suchasmethamphetamine)andmayactasanintrauterinestressorrather thanasadirecttoxin[2],animalmodelshaveshown thatprenatalexposuretococaineleadstochangesin dopaminereceptoractivityandsubcellulardistribution [24],andalterationsindendriticspinedensityinstriatal mediumspinyneurons[25].Thus,inthisstudy,we hypothesizedthatprenatalcocaineexposurewouldbe associatedwithsubtlestructuraldifferencesinthe morphologyofthecaudateandputamen.Specifically, wepredictedapositivecorrelationbetweenlevelsofprenatalcocaineexposureandextentofstructuralabnormalitiesinstriatalsurfacemorphology. Inadolescentswithprenatalcocaineexposure,wealso hypothesizedrelationshipsbetweenperformanceon neuropsychologicaltestsandregionalchangesinstriatal surfacemorphology.Inparticular,weexpectedthat deformationsinthedorsalcaudate(partoftheexecutive loop[26])wouldcorrelatewithdecreasedscoresontests ofexecutivefunctioning(Strooptest,TrailMakingtest partB),whereasdeformationsintheputamen(partof thefronto-striatalmotorloop[26])wouldcorrelatewith lowerscoresonavisuomotortask(TrailMakingtest partA). WealsoinvestigatedpossibleregionalvolumetricdifferencesbetweengroupsinsubcorticalandfrontalRoussotte etal.JournalofNeurodevelopmentalDisorders 2012, 4 :22Page2of10 http://www.jneurodevdisorders.com/content/4/1/22

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corticalregions.Wechosetorestrictouranalysesto theseparticularregionsofinterestbecausepreviousneuroimagingstudiesofstructuraland/ormetabolicbrain abnormalitiesinhumanswithprenatalcocaineexposure suggestedevidencefordifferencesintheseareas.That is,mostofthepublishedstructuralhumanstudieswith significantresultsreportedgroupdifferencesinfrontal [18,21]orsubcortical[12,20]structures.Thus,inthis study,weexpectedthatprenatalcocaineexposurewould beassociatedwithsubtlevolumetricdifferencesin frontalandsubcorticalareas.MethodsParticipantsFortyvolunteers,agerange14to16years,including28 adolescentswithprenatalcocaineexposureand12unexposedcontrolswerestudiedwithstructuralMRIcollectedattheUniversityofFlorida.Studyapprovalwas grantedbytheUniversityofFloridaInstitutionalReview Board,andafederalCertificateofConfidentialityprotectstheconfidentialityofthedata.Allparticipantswere theoffspringofwomenprospectivelyenrolledduring pregnancyinalongitudinalcohortstudyofthedevelopmentaleffectsofprenatalcocaineexposure[27].Aseparateinformedconsentfromthechild ’ sprimary caregiverandassentbythechildwereobtainedbefore thecurrentstudy.Detaileddrughistoriescoveringthe periodfrom3monthspriortogestationthroughbirth wereobtainedforallmothers.Prenatalcocaineexposure wasmeasuredastheratioofweeksofmaternalcocaine useduringpregnancyoverweeksofgestation.TheextentofPCEinexposedparticipantsrangedfrom0.04to 1,withameanratioof0.402andastandarddeviationof 0.25(Table1). Inadditiontoneuroimagingdata,biologicassayswere availableforparticipants(hairsamples,testedforcocaineatages10.5yearsand12.5years),aswellasneuropsychologicaldata.Participantswereadministereda batteryoftestsatthetimeofscanning,whichincludeda word-colorinterferenceStrooptestandaTrailMaking test.Wechosetoexaminethesetwoparticularmeasures ofneurocognitivefunctioninordertoinvestigaterelationshipsbetweenthemorphologyofstriatalstructures intheexecutiveandmotorloopsandtestsofresponse inhibition(Strooptest),taskswitching(TrailMakingtest partB)andvisuomotorfunction(TrailMakingtestpart A).ImageacquisitionNeuroimagingdatawerecollectedonaPhilips3T AchievaMRIscanner.ConventionalMRIsequences (axialT2multishotturbofieldecho)wereobtainedto detectpossibleconfoundingpathology.VolumetricT1weightedimageacquisitionusedamultishotgradient spinechopulsesequencewith8.1-msTR,3.7-msTE, 240240234matrix,1mmisotropicvoxelsize,and anacquisitiontimeof10min,14s.Imagepreprocessingandprocessing Surface-basedanalysesForthesurface-basedanalyses,eachbrainvolume wascorrectedforradiofrequencyfieldinhomogeneities [28]andplacedintothestandardcoordinatesystem oftheICBM-305averagebrainvolumeusingathreetranslationandthree-rotationrigid-bodytransformation [29].Thisprocedurecorrectsfordifferencesinhead alignmentbetweensubjectstoensurethatregionof interestmeasurementsarenotinfluencedbydifferent brainorientationsbetweensubjects[29]. Themethodsforsurfaced-basedimageanalysishave beendescribedindetailelsewhere[30-32].Briefly,two investigatorsblindtoexposurestatus(FFRandLS) devisedadetailedmanualtracingprotocolforthecaudateandputamen,whichincludeddirectionsaboutthe orderanddirectionoftracing,numerousvisualaidsto facilitatetheidentificationofanatomicallandmarks,and preciseinstructionsfordealingwithscanartifacts.Striatalcontourswerethenmanuallyoutlinedbythesame twoinvestigatorsoncontiguouscoronalslicesforevery subject(Figure1).Highintra-raterandinter-raterreliabilities(intraclasscorrelations>0.95)wereestablished basedonindependentblindedmeasurementofsixscans usedinthisstudy.Subsequently,manuallyderivedcontoursweretransformedinto3Dparametricsurfacemesh modelswithnormalizedspatialfrequencyofthesurface pointswithinandacrossbrainslices.Eachstructurewas madeintoaparametricgridcontaining100150grid pointsorsurfacenodes.Thisstepensuresprecisecomparisonofanatomybetweensubjectsateachsurface pointofthestructure.A3Dmedialcurvewascomputed alongthelongaxisforthesurfacemodelofeachstructureandradialdistancemeasures(distancefromthe medialcoretothesurface)wereestimatedandrecorded ateachcorrespondingsurfacepoint.Thesevalueswere usedtogenerateindividualdistancemaps,whichwere combinedtoproducecorrelationmapsallowingfor visualizationoftherelationshipsbetweenstriatalmorphologyand(1)levelsofprenatalcocaineexposure,and (2)neuropsychologicaltestscoresinexposedparticipants.Inallanalyses,quantitativemeasuresofprenatal exposuretotobacco,alcohol,andmarijuanawere includedasnuisancecovariates,aswellassex,cuberoot oftotalbrainvolume,andcocaineusebyadolescentparticipantsthemselves.Sincethismethodestimatesradial distancemeasures,anddistancefromthemedialcoreto thesurfaceisa1Dmeasure,cuberootofbrainvolume wasusedinplaceoftotalbrainvolume(a3Dmeasure), inordertomaketheunitscomparable.Roussotte etal.JournalofNeurodevelopmentalDisorders 2012, 4 :22Page3of10 http://www.jneurodevdisorders.com/content/4/1/22

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VolumetricanalysesPreprocessinganddefinitionofcorticalandsubcortical graymatterregionsonstructuralimageswereconducted intheUCLALaboratoryofNeuroImaging(LONI)PipelineProcessingEnvironment[33-35]andusingFreeSurfer ’ sautomatedbrainsegmentationsoftware(FreeSurfer 4.0.5,http://surfer.nmr.mgh.harvard.edu),asdescribedin theworkofFischlandDale[36-38].Weobtainedvolumemeasurementsofsevensubcorticalbrainregions (thalamus,caudate,putamen,pallidum,hippocampus, amygdala,andventraldiencephalon)aswellassix frontalcorticalregions(caudalmiddlefrontalcortex, rostralmiddlefrontalcortex,lateralorbitofrontalcortex, medialorbitofrontalcortex,superiorfrontalcortex,and frontalpoles).Duringpreprocessing,high-resolutionT1weightedimageacquisitionsforeachparticipantwere visuallyinspectedformotionartifactsbyatrainedrater basedona5-pointLikertscaleillustratingtheseverity ofmotioneffects.Noparticipantswererejecteddueto motionartifacts;however,onesubjectwasrejecteddue topoorgray-whitemattercontrast,andanothersubject wasrejectedbecausetherawimagedatafilesappeared corrupted.Inallremainingparticipants( n =40),theT1weightedimageswerebrainextracted,andgray-white matterboundarieswereautomaticallydelineated.All brainextractionswereinspectedvisuallyandcorrected manuallyasneeded. Volumesforthesevensubcorticalandsixfrontalcorticalregionsofinterest,aswellastotalintracranial volumeswerecalculatedusingFreeSurfer ’ sautomatic quantificationofcorticalandsubcorticalstructures.Proceduresaredescribedindetailelsewhere[38].Insummary,aneuroanatomicallabelwasassignedtoeach voxelinanindividual ’ sstructuralMRIbasedonprobabilisticinformationestimatedfromamanuallylabeled trainingset.Thismanuallylabeledtrainingsetisaresult ofvalidatedmethodsfromtheCenterofMorphometric Table1DemographicinformationandneuropsychologicaldataforsubjectsbygroupControlgroup (CON, n =12) Prenatalcocaineexposuregroup (PCE, n =28) Group differences Age(inwholeyears)14.70.4914.80.72 P =0.439 Gender7girls/18girls/ P =0.039a5boys10boys Cocaineexposure(weeksofmaternalcocaineusedividedbyweeksof gestation) None0.4020.25 P <0.001aTobaccoexposure(averagenumberofcigarettesperday)0.0200.0718.1557.79 P <0.001aAlcoholexposure(averageouncesperday)0.0070.0150.1990.371 P =0.011aMarijuanaexposure(averagenumberofjointsperday)0.0030.0100.1250.367 P =0.091bPostnatalcocaineexposure(hairsamplepositiveforcocaineatage 10.5yearsand/or12.5years) 6yes/6no10yes/18no P =0.030aTotalbrainvolume(inmm3)1,582,3501,559,794 P =0.846 188,214177,613 Word-colorinterferenceStrooptest,rawscore44.4179.5439.8579.15 P =0.605 TrailMakingtest,partAcompletiontime(inseconds)11.7504.3712.7864.78 P =0.882 TrailMakingtest,partBcompletiontime(inseconds)23.0007.8629.64311.00 P =0.360Meanvaluesaregivenwithstandarddeviation.aSignificantdifferencesbetweengroups( P <0.05).bTrend-leveldifferencesbetweengroups(0.05< P <0.10). Figure1 Regionofinterestdelineation. Theleftandright caudateandputamenweremanuallydelineatedoncontiguous coronalslicesfollowingadetailedprotocoldevisedbythe investigators Roussotte etal.JournalofNeurodevelopmentalDisorders 2012, 4 :22Page4of10 http://www.jneurodevdisorders.com/content/4/1/22

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Analysis(http://www.cma.mgh.harvard.edu).Todisambiguatetheoverlapinintensitiesbetweendifferent anatomicalstructures,FreeSurferutilizedspatialinformation.Twotransformationswereperformed.First, anoptimallineartransformationwascarriedoutby maximizingthelikelihoodofthenativeimagegivena manuallylabeledatlas.Second,anon-lineartransformationwasexecutedontheoutputofthepriorregistrationstep.Finally,aBayesianparcellationwasconducted byusingpriorspatialinformation[39,40].Attheendof thisprocessingstream,threeprobabilitieswerecalculatedforeachvoxel:(1)theprobabilityofthevoxel belongingtoeachofthelabelclasses,basedonitslocation,(2)theneighborhoodfunction,usedtodetermine thelikelihoodthatthevoxelsbelongtoaclass,basedon theclassificationofneighboringvoxels,and(3)theresultoftheprobabilitydistributionfunctionforeach voxelbasedonitsintensity. Theaccuracyofthistechniquewasshowntobesimilartomanualmethods.Theautomatedsegmentations havebeenfoundtobestatisticallyindistinguishablefrom manuallabeling[38].Beingcompletelyautomated,Freesurfervolumeestimatesarehighlyreliable.Nonetheless, inthecurrentstudy,eachbrainimagewasvisually inspectedforvalidityofallregionsbyasingletrained blindrater.Inoverone-thirdofsubjects,thesegmentationsofthecaudateandputamenwerejudgedunsatisfactory,duetopulsationartifactsaroundthestriatumon thehigh-resolutionT1-weightedimages.Therefore,the volumesofthecaudateandputamenwerecalculated fromthemanuallyderivedcontours(obtainedinthe surface-basedanalyses)forallsubjects( n =40),and thesevalueswereusedinplaceoftheFreeSurferoutputs inallstatisticalanalyses.Statisticalanalysesofdemographic,neuropsychological, andvolumetricdataStatisticalanalyseswereconductedusingSYSTAT12.0 andSPSS20.0.Groupdifferencesinage,totalbrainvolume,neuropsychologicaltestperformance,andprenatal exposuretotobacco,alcohol,andmarijuanawereevaluatedusingtwo-sampleindependentt-tests.Groupdifferencesingenderandpostnatalcocaineexposurewere assessedwithaPearsonChi-SquareTest. Involumetricanalyses,groupdifferencesinregional brainvolumeswereevaluatedusingseparateone-way ANOVAtestsforeachindividualregionofinterest.In allanalyses,prenatalexposuretococainewasmodeled astheindependentvariable,whilethevolume(inmm3) oftheregionofinterestwasusedasthedependentvariable.Allanalysesincludedthefollowingcovariates:prenatalexposuretoalcohol,tobacco,andmarijuana,in additiontosex,totalbrainvolume,andcocaineuseby participantsthemselves(asmeasuredbyapositivehair sampleat10.5and/or12.5yearsofage).Two-wayANOVASweresubsequentlyperformedinordertoexamine possibleinteractionsbetweenpre-andpostnatalcocaine exposure. Associationsbetweenneuropsychologicaltestscores andlevelsofprenatalcocaineexposurewereinvestigated withmultipleregressionanalysesusingthefollowing equation:Performance=Constant+LevelofPrenatalCocaine Exposure+PrenatalAlcohol Exposure+PrenatalTobacco Exposure+PrenatalMarijuanaExposure+Sex+CocaineUse byParticipants(asmeasuredbyapositivehairsampleat10.5 and/or12.5yearsofage).ResultsDemographicsDemographicdescriptorsarereportedinTable1.The PCEandCONgroupsdidnotdifferfromeachotherin age( P =0.439)butshowedasignificantdifferencein genderdistribution( P =0.039),withtheexposedgroup comprisingmoregirls.Thetwogroupssignificantlydifferedfromeachotherinprenatalexposuretotobacco ( P <0.001)andalcohol( P =0.011),withthePCEgroup showingsignificantlyhigherlevelsofexposuretothese drugsthanparticipantsintheCONgroup.Wealso reportedatrend-leveldifferenceinprenatalexposureto marijuana( P =0.091)andasignificantdifferenceinpostnatalexposuretococaine( P =0.030)assessedby cocaine-positivehairsamplesatage10.5yearsand/or 12.5years.ThePCEgrouptendedtohavehigherlevels ofprenatalmarijuanaexposure,andwhiletheCON groupcomprisedanequalnumberofparticipantswith andwithoutpostnatalcocaineexposure,thePCEgroup includedalmosttwiceasmanynon-usersasusers.The twogroupsdidnotdifferintotalbrainvolume ( P =0.846).Nevertheless,inallanalysespresentedbelow, totalbrainvolumewasusedasacovariatealongwith sex,postnatalcocaineexposure,andprenatalexposure tootherdrugsofabuseinordertoeliminateanyvarianceduetopossibledisparitiesinoverallbrainvolume withingroups.Surface-deformationanalyses MaineffectsofprenatalcocaineexposureTheoverallvolumesofthecaudateandputamendidnot significantlydifferbetweenparticipantswithprenatalcocaineexposure(thePCEgroup)andcontrols(theCON group).Inaddition,differencesincaudateandputamen morphologybetweenthesetwogroupswerenonsignificantafterregressingoutprenatalexposureto otherdrugsofabuse,totalbrainvolume,sex,andcocaineuse,evenwhenprenataltobaccoexposurewasnot includedasanuisancecovariate.However,3Dsurface statisticsrevealedsignificant( P <0.05,uncorrected) effectsoftheamountofprenatalexposuretococaineRoussotte etal.JournalofNeurodevelopmentalDisorders 2012, 4 :22Page5of10 http://www.jneurodevdisorders.com/content/4/1/22

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onregionalpatternsofstriatalmorphologyacrossall participants. Higherlevelsofprenatalcocaineexposurewereassociatedwithcontractionofstriatalsurfacesintheventromedialandinthedorsalcaudate,andsomeregionsof expansionintheventrolateralcaudate.Theseeffects werestrongerintheleftcaudate(Figures2.2and2.3). Similarbutlesspronouncedresultswereobservedinthe rightcaudate(datanotshown). Greaterprenatalcocaineexposurewasassociatedwith contractionofstriatalsurfacesintheposteriorputamen andintheventrolateralanddorsomedialputamen. Higherlevelsofprenatalcocaineexposurewereassociatedwithlargeareasofexpansionintheanteriorputamen,aswellasinthedorsolateralandventromedial putamen.Theseeffectswerestrongerintherightputamen(Figures2.4and2.5).Similarbutlesspronounced resultswereobservedintheleftputamen(datanot shown).Comparablecorrelationalmapsintermsof strengthandextentwereobtainedintheleftandright caudateandputamenwhenprenataltobaccoexposure wasnotincludedasanuisancecovariate(datanot shown).Theseresultsdidnotremainsignificantafter correctingformultiplespatiallycorrelatedcomparisons usingpermutationtesting.NeuropsychologicalcorrelatesofstriatalmorphologyFollowingtheseinitialanalyses,weexaminedthetwo ROIsthatshowedthemostsignificanteffects(leftcaudateandrightputamen),andinvestigatedrelationships betweenneuropsychologicaltestscoresandregional deformationsofthestriatalsurfaceinexposedsubjects. Specifically,wefirstexaminedcorrelationsbetweenmeasuresofexecutivefunctioningandregionaldeformation oftheleftcaudatesurface.Higherscores(betterperformance)ontheStrooptest(Figure2.6)wereassociatedwithlargervolumeinsubregionsofthedorsal caudate,whilelongerresponsetimes(lowerperformance)onpartBoftheTrailMakingtest(Figure2.7)correlatedwithlargervolumeinotherpartsofthedorsal caudate. Wealsoinvestigatedcorrelationsbetweenameasure ofvisuomotorfunctioningandregionaldeformationof therightputamensurface.Longerresponsetimeson partAoftheTrailMakingtestwereassociatedwithlargervolumeofthemedialputamen,mostlyintheposteriorregion(Figure2.8).Noneoftheseresultsremained significantafterperformingpermutationtestinginorder tocorrectformultiplespatiallycorrelatedcomparisons.VolumetricanalysesIntheseanalyses,weexaminedgroupdifferencesinregionalbrainvolumesbetweenthePCEgroupandthe CONgroup.Asinthesurface-deformationanalyses,in additiontosex,totalbrainvolume,andcocaineuseby theparticipantsthemselves,wealsousedprenatalexposuretoalcohol,tobacco,andmarijuanaasnuisancecovariatesinallanalysesinanattempttodetectthespecific effectsofprenatalcocaineexposure. Consistentwiththesurface-basedanalysesinwhich wefoundnosignificantgroupdifferencesinoverall volumesofthecaudateandputamenbasedon manually-derivedcontour,hereweobservednosignificantchangesinthevolumeofanysubcorticalregionof interestinthePCEgroupcomparedtotheCONgroup inanalysesbasedonautomatedsegmentation.However, wedetectedgroupdifferencesinthevolumesofsome frontalcorticalregions. Weobservedsignificant(uncorrected)reductionsin regionalvolumesintheleft( P =0.046)andright ( P =0.036)caudalmiddlefrontalcortices,andintheleft lateralorbitofrontalcortex( P =0.048),inparticipants withprenatalcocaineexposurecomparedtocontrols (Figure3).Ontheotherhand,intheleft( P =0.072)and right( P =0.098)frontalpoles,weobservedtrend-level increasesinregionalbrainvolumesinthePCEgroup comparedtocontrols(Figure3). Wefoundnosignificantmaineffectsofpostnatalcocaineexposure(cocaineusebyparticipants)onthevolumeofanyfrontalcorticalregion,andtherewereno significantinteractionsbetweenpre-andpostnatalcocaineexposure.Moreover,neuropsychologicalperformanceontheword-colorinterferenceStroopTest,andon partsAandBoftheTrailMakingTestdidnotdiffer significantlybetweenthePCEandcontrolgroups (Table1);andtherewerenosignificantcorrelations betweenlevelsofprenatalcocaineexposureandneuropsychologicaltestscores,afterco-varyingforprenatal exposuretootherdrugsofabuse,sex,andpostnatalcocaineexposure.DiscussionandconclusionsTakentogether,theseresultssuggestthatprenatalcocaineexposuremayleadtoregionallyspecificpatterns ofmorphologicalchangesinthestriatumandsubtle volumetricdifferencesincertainfrontalcorticalregions. Themostsignificantfindinginouranalysesofcaudate morphologywasanassociationbetweenlevelsofprenatalcocaineexposureandsurfacecontractioninthe ventromedialanddorsolateralcaudate.Theventromedialcaudateispartofthelateralorbitofrontalstriatal loop,whichisinvolvedintheregulationofemotionand socialbehavior[26].Interestingly,wealsoreportedregionalvolumechangesintheleftlateralorbitofrontal cortexinthePCEgroupcomparedtocontrols.The dorsolateralcaudate,ontheotherhand,ispartofthe executiveloopassociatedwithhigher-ordercognitive functions[26],andwealsofoundlocalvolumetricRoussotte etal.JournalofNeurodevelopmentalDisorders 2012, 4 :22Page6of10 http://www.jneurodevdisorders.com/content/4/1/22

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differencesinthefrontalpoles,whichplayarolein spatialworkingmemory,responseinhibition[41],and theevaluationofself-generated[42]andgoal-directed [43]decisions.Therefore,thefindingspresentedhere mayrepresentsomeoftheneuralcorrelatesofthedifficultiesinemotionalregulation[5,6]andimpairmentsin attention,responseinhibition[7],andvisuospatialworkingmemory[44]thathavebeenreportedinchildren withprenatalcocaineexposure. Theputamenispartofthefronto-striatalloop involvedinmotorcontrol[26].Mostpremotorareaprojectionsaredirectedtothemedialputamen,andmost supplementarymotorareaprojectionsterminateinthe posteriorputamen[45],andinbothsubregionswe foundthatgreaterprenatalcocaineexposurewasassociatedwithacontractionofstriatalsurfaces.Inaddition, weobservedsignificantreductionsinregionalvolumes inthebilateralcaudalmiddlefrontalcorticesinthePCE groupcomparedtocontrols,andthecaudalpartofthe middlefrontalgyruscorrespondstopremotorbrain areas.Therefore,itispossiblethatthesefindingsmaybe relatedtothedeficitsinfinemotorcoordinationthat havebeenreportedinthispopulation[10]. Whilethedirectionofchangesinstriatalsurfacestructurewerenotpredicted apriori ,itshouldbenotedthat prenatalcocaineexposurewasassociatedwithsurface contractioninsomesubregions,andexpansionin others.Thoughthebiologicalmechanismscontributing tothesefindingsremainunclear,thebidirectionalnature ofregionaleffectsmayexplainwhyoveralldifferencesin striatalvolumewerenotdetectedinthisstudybetween exposedandcontrolparticipantsineitherthesurfaceFigure2 2,3,4,and5:Uncorrectedsurfacemapsdepictingrelationshipsbetweenlevelsofprenatalcocaineexposureandregional deformationsofstriatalsurface( n =40). Blue-to-light-blueshadingindicatesregionswherehigherlevelsofprenatalcocaineexposureare associatedwithcontractionofstriatalsurfaces.Red-to-yellowshadingdisplaysregionswherehigherexposurelevelsareassociatedwith expansionofthesurfaces.Forallstatisticalmaps,thecolorbarencodestheuncorrected P values( P <0.05)fortheobservedeffects. 6,7,8: Uncorrectedsurfacemapsdepictingrelationshipsbetweenneuropsychologicalscores(6:Stroop,7:TrailsA,8:TrailsB)andregional deformationsofstriatalsurfaceinexposedsubjects( n =28) .Red-to-yellowshadingdisplaysregionswherehigherscores(betterperformance ontheStrooptestbutlongerresponsetimesontheTrailstest)arecorrelatedwithlargerregionalstriatalvolumes.Fewnegativecorrelations wereobservedintheseanalyses.Forallstatisticalmaps,thecolorbarencodestheuncorrected P values( P <0.05)fortheobservedeffects. Figure3 Groupdifferencesinfrontalcorticalbrainvolumes (uncorrectedresults). Blueandgreenshadingindicatesregions wherethePCEgroupshoweddecreasedvolumescomparedto controls( P <0.05)aftercontrollingforprenatalexposuretotobacco, alcohol,andmarijuanaaswellassex,totalbrainvolume,anddrug usebyparticipants.RedshadingindicatesregionswherethePCE groupshowedtrendsforincreasedvolumescomparedtocontrols ( P <0.10),usingthesamecovariates.Thickerblackcontours delineateallofthefrontalregionsofinterestthatwereexaminedin theseanalyses Roussotte etal.JournalofNeurodevelopmentalDisorders 2012, 4 :22Page7of10 http://www.jneurodevdisorders.com/content/4/1/22

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basedorthevolumetricanalyses.Similarly,whilewedid nothavespecificpredictionsaboutthedirectionof changesinregionalfrontalcorticalvolumes,prenatalcocaineexposurewasshowntobeassociatedwithvolume reductionsinsomefrontalsubregions,andincreased volumesinothers.Thereasonsforthisdiscrepancyremainunclear,butthelocalizedandbidirectionalnature offrontalcorticaleffectsmayexplaininpartwhycertain neuroimagingstudiesfoundsignificantstructuraldifferencesinthefrontallobes,whileothersreportednegative results. Consistentwithourpredictions,weobservedverynarrowlylocalizedcorrelationsbetweenmeasuresofexecutivefunctioningandregionaldeformationofthedorsal caudatesurface.However,thespecificareaswherethis associationwassignificantdidnotcorrespondexactlyto thesubregionsofthedorsalcaudatewherehigherlevels ofprenatalexposurewerecorrelatedwithgreaterdysmorphology.Thespecificareasofthedorsalcaudate showingcorrelationswithmeasuresofexecutivefunctioningalsodifferedbytask:theyweremoresuperior andmedialfortheStrooptestthanforpartAofthe TrailMakingtest. Aspredicted,wealsoobservedamarginallysignificant correlationbetweenameasureofvisuomotorperformance andregionaldeformationof theputamensurface,which wassignificantinthemedialandposteriorputamen,where mostpremotorandsupplementarymotorareaprojections terminate[45],suggestingapossibleassociationbetween neurologicalandbehavioralabnormalities. However,whiletheseresultssuggestthatprenatal exposuretococainemayaffectthemorphologyofthe striatumandregionalfrontallobevolumes,itisimportanttokeepinmindthattheeffectsizesweresmallfor alloftheresultsreportedhere,andthatthesurfacedeformationandvolumetricmapswerenotcorrected formultiplespatiallycorrelatedcomparisons.Nevertheless,thefactthatwereportedsubtlechangesconsistent withfindingsfromtheanimalliteratureandwithour a-priori hypotheses,suggeststhatthesedifferencesmay bedueinparttothespecificeffectsofprenatalcocaine exposure. WefoundnoassociationbetweenPCEandneurologicaltestscores,whichsuggeststhatbrainstructure maybeamoresensitivebiomarkertolevelsofprenatal cocaineexposurethanneuropsychologicaltestperformance.Thisisconsistentwithfindingsfromtheanimal literature,suggestingthatcognitivetestsmaybemore sensitivetothepatternofmaternalconsumptionthanto theamountofcocaineintake,eveninthepresenceof neurobiologicalalterations[46].Despiteshowingevidenceforabnormalneuronalmigrationandcortical laminationaswellasneurochemicaldifferences,rhesus monkeyswithboth ‘ highdoses ’ and ‘ lowdoses ’ ofPCE donotsignificantlydifferfromcontrolsincognitiveperformance,whereasmonkeysinthe ‘ escalatingdose ’ groupshowimpairments[46]. Itshouldbenotedthatwedidnothavedataabout participants ’ useofotherdrugs,thuswecannotexclude thepossibilitythatpostnatalexposuretoothersubstancesofabusemayhaveaffectedthefindings.Another importantlimitationisthatneuroimagingdatawasavailableforonly12adolescentcontrols.Thoughwecannot ruleouttheeventualitythatalargercontrolgroup wouldhaveallowedforthedetectionofslightlymore robustgroupdifferences,inthecontextoftheexisting literature,thesefindingssupportthenotionthatthe effectsofPCEonbrainstructuremaybequitesubtle. Analternativeexplanationtofindingsofmodesteffects inthecurrentstudymaybethatthemarginallysignificantalterationsobservedsimplyreflectrelativelyminor consequencesofPCEonbraindevelopment.Somepublicationssuggestedthatcocainemaybearelativelyweak teratogenwithfewobservableneurologicalorbehavioral consequencesinhumans[47],unlikeothercommon substancesofabuseduringpregnancy,whichhavebeen moreconvincinglylinkedtopsychopathologyrisk,such asalcohol[48]andnicotine[49]. Thesmalleffectsizesobservedhereaswellasregional differencesinthedirectionofeffectsmayhelpexplain whypriorinvestigationsoftheconsequencesofprenatal cocaineexposureonbrainstructurehaveyieldedsomewhatconflictingresults.Althoughanimalstudiesof PCE,particularlystudiesofnon-humanprimates,clearly demonstratethepotentialofprenatalcocaineexposure tointerferewithbraindevelopmentatacellularandbiochemicallevelinvariousbrainregions[24,25,47,50-52], theyalsosuggestthatthetypesandseverityofPCE effectslargelydependontheroute,dose,gestational period,andpatternofconsumption[46].Thesecouldbe additionalcontributingfactorstothediscrepanciesin theexistinghumanneuroimagingliterature,andtothe smalleffectsizesreportedhere. Thus,itisimportantthatfutureneuroimagingstudies ofprenatalcocaineexposurewithlargersamplescollect informationaboutadolescentparticipants ’ useofother substances,specificpatternsandtimingofmaternalcocaineconsumption,andaimtointegrateobservations fromdifferentbrainimagingmodalities.Thiswillhelp determinehowstructural,metabolic,andfunctional brainabnormalitiesresultingfromPCErelatetoreallifedifficultiesthesechildrenfaceoutsidethescanner, assubtleneurologicalchangesmayverywellbeassociatedwithimportantbehavio ral,cognitive,oremotional impairments. Althoughseveralpromisingpsychosocialprevention strategiesforpregnantwomenaddictedtococainehave beenidentified[53],effectiveremediationstrategiesandRoussotte etal.JournalofNeurodevelopmentalDisorders 2012, 4 :22Page8of10 http://www.jneurodevdisorders.com/content/4/1/22

PAGE 9

treatmentsforprenatallyexposedchildrenremaintobe developed.Theimprovementofsuchstrategieswillrequirethatwegainabetterunderstandingofthespecific, localizedandperhapssubtleneurologicalabnormalities resultingfromprenatalcocaineexposureinorderto facilitatethetranslationofresearchfindingstoclinical practice.Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. Authors ’ contributions FRanalyzedandinterpretedthedataandwasthemainwriterofthe manuscript.LShelpedwithdataprocessingandanalysis.TWhelpedwith datacollectionanddatainterpretation.KNhelpedwithtechnicalaspectsof dataanalysisanddatainterpretation.CLhelpedwithdatainterpretationand helpedrevisethemanuscript.MBhelpedwithdatacollectionand interpretation.FDEhelpedwithdatacollectionandinterpretation.ERSwas theprincipalinvestigator,whosupervisedthewholeproject,andhelped writethemanuscript.Allauthorsreadandapprovedthefinalmanuscript. Acknowledgments ThisworkwassupportedbyNationalInstituteofDrugAbuseGrantsR21 DA15878andR01DA017831andtheMarchofDimes(6FY2008-50)awarded toERS.AdditionalsupportwasprovidedbyGrantsR21DA027561awarded toTWandERSandR01DA05854awardedtoFDEandMB. Authordetails1DepartmentofNeurology,UniversityofCalifornia,LosAngeles,CA,USA.2DevelopmentalCognitiveNeuroimagingLaboratory(DCNL),Departmentof Pediatrics,UniversityofSouthernCalifornia,LosAngeles,CA,USA.3DepartmentofPediatrics,UniversityofFlorida,GainesvilleFL,USA.4LaboratoryofNeuroImaging,DepartmentofNeurology,Universityof California,LosAngeles,CA,USA. Received:26April2012Accepted:19July2012 Published:7August2012 References1.AmaraSG,SondersMS: Neurotransmittertransportersasmolecular targetsforaddictivedrugs. DrugAlcoholDepend 1998, 51: 87 – 96. 2.LesterBM,PadburyJF: Thirdpathophysiologyofprenatalcocaine exposure. DevNeurosci 2009, 31: 23 – 35. 3.BadaHS,DasA,BauerCR,ShankaranS,LesterB,LaGasseL,HammondJ, WrightLL,HigginsR: Impactofprenatalcocaineexposureonchild behaviorproblemsthroughschoolage. Pediatrics 2007, 119: e348 – e359. 4.LinaresTJ,SingerLT,KirchnerHL,ShortEJ,MinMO,HusseyP,MinnesS: Mentalhealthoutcomesofcocaine-exposedchildrenat6yearsofage. JPediatrPsychol 2006, 31: 85 – 97. 5.LiZ,ColesCD,LynchME,HamannS,PeltierS,LaConteS,HuX: Prenatal cocaineexposurealtersemotionalarousalregulationanditseffectson workingmemory. NeurotoxicolTeratol 2009, 31: 342 – 348. 6.EidenRD,McAuliffeS,KachadourianL,ColesC,ColderC,SchuetzP: Effects ofprenatalcocaineexposureoninfantreactivityandregulation. NeurotoxicolTeratol 2009, 31: 60 – 68. 7.AccorneroVH,AmadoAJ,MorrowCE,XueL,AnthonyJC,BandstraES: Impactofprenatalcocaineexposureonattentionandresponse inhibitionasassessedbycontinuousperformancetests. 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Abstract
Background
Published structural neuroimaging studies of prenatal cocaine exposure (PCE) in humans have yielded somewhat inconsistent results, with several studies reporting no significant differences in brain structure between exposed subjects and controls. Here, we sought to clarify some of these discrepancies by applying methodologies that allow for the detection of subtle alterations in brain structure.
Methods
We applied surface-based anatomical modeling methods to magnetic resonance imaging (MRI) data to examine regional changes in the shape and volume of the caudate and putamen in adolescents with prenatal cocaine exposure (n = 40, including 28 exposed participants and 12 unexposed controls, age range 14 to 16 years). We also sought to determine whether changes in regional brain volumes in frontal and subcortical regions occurred in adolescents with PCE compared to control participants.
Results
The overall volumes of the caudate and putamen did not significantly differ between PCE participants and controls. However, we found significant (P <0.05, uncorrected) effects of levels of prenatal exposure to cocaine on regional patterns of striatal morphology. Higher levels of prenatal cocaine exposure were associated with expansion of certain striatal subregions and with contraction in others. Volumetric analyses revealed no significant changes in the volume of any subcortical region of interest, but there were subtle group differences in the volumes of some frontal cortical regions, in particular reduced volumes of caudal middle frontal cortices and left lateral orbitofrontal cortex in exposed participants compared to controls.
Conclusions
Prenatal cocaine exposure may lead to subtle and regionally specific patterns of regional dysmorphology in the striatum and volumetric changes in the frontal lobes. The localized and bidirectional nature of effects may explain in part the contradictions in the existing literature.
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Roussotte, Florence
Soderberg, Lindsay
Warner, Tamara
Narr, Katherine
Lebel, Catherine
Behnke, Marylou
Davis-Eyler, Fonda
Sowell, Elizabeth
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p Adolescents with prenatal cocaine exposure show subtle alterations in striatal surface morphology and frontal cortical volumes
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au id A1 snm Roussottefnm Florenceinsr iid I1 I2 email florence.roussotte@gmail.com
A2 SoderbergLindsaylsoderberg@chla.usc.edu
A3 WarnerTamaraI3 warnertd@peds.ufl.edu
A4 NarrKatherineI4 narr@loni.ucla.edu
A5 LebelCatherinecatherine.lebel@gmail.com
A6 BehnkeMaryloubehnkem@peds.ufl.edu
A7 Davis-EylerFondaeylerfd@peds.ufl.edu
A8 ca yes SowellElizabethesowell@chla.usc.edu
insg
ins Department of Neurology, University of California, Los Angeles, CA, USA
Developmental Cognitive Neuroimaging Laboratory (DCNL), Department of Pediatrics, University of Southern California, Los Angeles, CA, USA
Department of Pediatrics, University of Florida, Gainesville, FL, USA
Laboratory of NeuroImaging, Department of Neurology, University of California, Los Angeles, CA, USA
source Journal of Neurodevelopmental Disorders
issn 1866-1955
pubdate 2012
volume 4
issue 1
fpage 22
url http://www.jneurodevdisorders.com/content/4/1/22
xrefbib pubidlist pubid idtype doi 10.1186/1866-1955-4-22pmpid 22958316
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kwdg
kwd Prenatal drug exposure
Cocaine
Striatum
Frontal lobes
abs
sec
st
Abstract
Background
Published structural neuroimaging studies of prenatal cocaine exposure (PCE) in humans have yielded somewhat inconsistent results, with several studies reporting no significant differences in brain structure between exposed subjects and controls. Here, we sought to clarify some of these discrepancies by applying methodologies that allow for the detection of subtle alterations in brain structure.
Methods
We applied surface-based anatomical modeling methods to magnetic resonance imaging (MRI) data to examine regional changes in the shape and volume of the caudate and putamen in adolescents with prenatal cocaine exposure (n = 40, including 28 exposed participants and 12 unexposed controls, age range 14 to 16 years). We also sought to determine whether changes in regional brain volumes in frontal and subcortical regions occurred in adolescents with PCE compared to control participants.
Results
The overall volumes of the caudate and putamen did not significantly differ between PCE participants and controls. However, we found significant (it P <0.05, uncorrected) effects of levels of prenatal exposure to cocaine on regional patterns of striatal morphology. Higher levels of prenatal cocaine exposure were associated with expansion of certain striatal subregions and with contraction in others. Volumetric analyses revealed no significant changes in the volume of any subcortical region of interest, but there were subtle group differences in the volumes of some frontal cortical regions, in particular reduced volumes of caudal middle frontal cortices and left lateral orbitofrontal cortex in exposed participants compared to controls.
Conclusions
Prenatal cocaine exposure may lead to subtle and regionally specific patterns of regional dysmorphology in the striatum and volumetric changes in the frontal lobes. The localized and bidirectional nature of effects may explain in part the contradictions in the existing literature.
bdy
Background
Cocaine is a central nervous system stimulant that binds to and blocks the activity of monoamine transporters, resulting in increased synaptic and extracellular levels of dopamine, norepinephrine, and serotonin
abbrgrp
abbr bid B1 1
. The animal literature suggests that prenatal cocaine exposure (PCE) affects brain development in various ways, in particular through diverse neurochemical and vasocontrictive mechanisms, as well as through epigenetic changes in placental DNA associated with the disruption of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in lasting emotional and behavioral dysregulation
B2 2
.
The neurobehavioral effects of PCE have also been documented in humans. In particular, children exposed to cocaine in utero exhibit more negative behavioral functioning
B3 3
B4 4
than unexposed controls, and experience difficulties with emotion regulation
B5 5
B6 6
. They make more errors during attention and response inhibition tasks than non-exposed controls
B7 7
B8 8
. They also show deficits in procedural learning, visual motor, and motor skills
B9 9
B10 10
. Less is known about the neurobehavioral phenotype of adolescents with prenatal cocaine exposure, though one study suggests impairments in incidental memory
B11 11
.
The functional magnetic resonance imaging (fMRI) literature of PCE in humans, though small, suggests the existence of various types of functional brain abnormalities in youth with prenatal exposure to cocaine. For example, an earlier perfusion fMRI study reported changes in global cerebral blood flow (CBF) in the PCE group compared to controls
B12 12
. While one blood oxygen level-dependent (BOLD) fMRI study found only trend-level differences in functional brain activation during a non-spatial working-memory task between PCE participants and controls
B13 13
, two other BOLD fMRI investigations reported significant differences between groups. Specifically, one study found group differences in task-related activation during a response inhibition task
B14 14
, and another reported differences in activation patterns associated with emotion-memory interactions
5
. Finally, three recent studies found group differences in functional and/or effective connectivity between participants with PCE and controls
B15 15
B16 16
B17 17
.
The neuroimaging literature addressing the structural effects of prenatal cocaine exposure on human brain development has yielded more inconsistent findings. A diffusion tensor imaging (DTI) study found higher average diffusion coefficients in the PCE group in left frontal callosal and right frontal projection fibers, suggesting suboptimal white matter development in these regions, regardless of prenatal exposure to other drugs of abuse
B18 18
. Another investigation reported white matter reductions in the volume of the corpus callosum and gray matter reductions in occipital and parietal lobes, in PCE participants compared to controls
B19 19
. The amount of cocaine ingested by the mother during pregnancy predicted the area of the corpus callosum and remained significant after controlling for prenatal exposure to other drugs
19
. Two additional studies reported changes in subcortical structures, specifically decreased caudate volumes
12
B20 20
, and increased gray matter volumes in the amygdala
12
in youth with prenatal exposure to cocaine, though these studies did not control for other gestational drug exposures.
In contrast, there are several reports of negative findings with regards to structural brain differences in PCE. One study combining structural magnetic resonance imaging (sMRI) and magnetic resonance spectroscopy (MRS) found no structural or volumetric abnormalities in any brain region in the PCE group
B21 21
. The authors did observe an increase in frontal white matter creatine levels in the exposed group compared to controls, but did not control for prenatal exposure to tobacco or alcohol
21
. Another whole-brain volumetric study found no significant structural differences between PCE participants and controls after controlling for exposure to other drugs of abuse, suggesting that none of the initially observed brain volume reductions in the exposed group could be attributed to the specific teratogenic effects of cocaine
B22 22
. In addition, a recent DTI study which included prenatal tobacco exposure as a nuisance covariate reported no significant differences between adolescents with PCE and control participants in any subregion of the corpus callosum
B23 23
.
To help clarify these discrepancies in the structural neuroimaging literature, here, we investigated the neurological consequences of prenatal exposure to cocaine using methodologies that allow for the detection of more subtle alterations in brain structure. We applied advanced surface-based anatomical modeling methods to MRI data, in order to examine regional changes in the shape and volume of the caudate and putamen. In addition, we examined regional volumetric differences between participants with prenatal cocaine exposure and unexposed controls in several subcortical and frontal cortical regions of interest implicated by some, though not all prior studies as indicated above.
Because of the mechanisms of action of cocaine, we focused our surface-based analyses on dopamine-rich striatal regions. Although cocaine is less neurotoxic than other stimulant drugs of abuse (such as methamphetamine) and may act as an intrauterine stressor rather than as a direct toxin
2
, animal models have shown that prenatal exposure to cocaine leads to changes in dopamine receptor activity and subcellular distribution
B24 24
, and alterations in dendritic spine density in striatal medium spiny neurons
B25 25
. Thus, in this study, we hypothesized that prenatal cocaine exposure would be associated with subtle structural differences in the morphology of the caudate and putamen. Specifically, we predicted a positive correlation between levels of prenatal cocaine exposure and extent of structural abnormalities in striatal surface morphology.
In adolescents with prenatal cocaine exposure, we also hypothesized relationships between performance on neuropsychological tests and regional changes in striatal surface morphology. In particular, we expected that deformations in the dorsal caudate (part of the executive loop
B26 26
) would correlate with decreased scores on tests of executive functioning (Stroop test, Trail Making test part B), whereas deformations in the putamen (part of the fronto-striatal motor loop
26
) would correlate with lower scores on a visuomotor task (Trail Making test part A).
We also investigated possible regional volumetric differences between groups in subcortical and frontal cortical regions. We chose to restrict our analyses to these particular regions of interest because previous neuroimaging studies of structural and/or metabolic brain abnormalities in humans with prenatal cocaine exposure suggested evidence for differences in these areas. That is, most of the published structural human studies with significant results reported group differences in frontal
18
21
or subcortical
12
20
structures. Thus, in this study, we expected that prenatal cocaine exposure would be associated with subtle volumetric differences in frontal and subcortical areas.
Methods
Participants
Forty volunteers, age range 14 to 16 years, including 28 adolescents with prenatal cocaine exposure and 12 unexposed controls were studied with structural MRI collected at the University of Florida. Study approval was granted by the University of Florida Institutional Review Board, and a federal Certificate of Confidentiality protects the confidentiality of the data. All participants were the offspring of women prospectively enrolled during pregnancy in a longitudinal cohort study of the developmental effects of prenatal cocaine exposure
B27 27
. A separate informed consent from the child’s primary caregiver and assent by the child were obtained before the current study. Detailed drug histories covering the period from 3 months prior to gestation through birth were obtained for all mothers. Prenatal cocaine exposure was measured as the ratio of weeks of maternal cocaine use during pregnancy over weeks of gestation. The extent of PCE in exposed participants ranged from 0.04 to 1, with a mean ratio of 0.402 and a standard deviation of 0.25 (Table
tblr tid T1 1).
table
Table 1
caption
b Demographic information and neuropsychological data for subjects by group
tgroup align left cols 4
colspec colname c1 colnum 1 colwidth 1*
c2 2
c3 3
c4
thead valign top
row rowsep
entry
Control group (CON,
n
 = 12)
Prenatal cocaine exposure group (PCE,
n
 = 28)
Group differences
tfoot
Mean values are given with standard deviation.
sup aSignificant differences between groups (P <0.05).
bTrend-level differences between groups (0.05 < P < 0.10).
tbody
Age (in whole years)
14.7 ± 0.49
14.8 ± 0.72
P = 0.439
morerows
Gender
7 girls/
18 girls/
P = 0.039a
5 boys
10 boys
Cocaine exposure (weeks of maternal cocaine use divided by weeks of gestation)
None
0.402 ± 0.25
P <0.001a
Tobacco exposure (average number of cigarettes per day)
0.020 ± 0.071
8.155 ± 7.79
P <0.001a
Alcohol exposure (average ounces per day)
0.007 ± 0.015
0.199 ± 0.371
P = 0.011a
Marijuana exposure (average number of joints per day)
0.003 ± 0.010
0.125 ± 0.367
P = 0.091b
Postnatal cocaine exposure (hair sample positive for cocaine at age 10.5 years and/or 12.5 years)
6 yes / 6 no
10 yes / 18 no
P = 0.030a
Total brain volume (in mm3)
1,582,350
1,559,794
P = 0.846
± 188,214
± 177,613
Word-color interference Stroop test, raw score
44.417 ± 9.54
39.857 ± 9.15
P = 0.605
Trail Making test, part A completion time (in seconds)
11.750 ± 4.37
12.786 ± 4.78
P = 0.882
Trail Making test, part B completion time (in seconds)
23.000 ± 7.86
29.643 ± 11.00
P = 0.360
In addition to neuroimaging data, biologic assays were available for participants (hair samples, tested for cocaine at ages 10.5 years and 12.5 years), as well as neuropsychological data. Participants were administered a battery of tests at the time of scanning, which included a word-color interference Stroop test and a Trail Making test. We chose to examine these two particular measures of neurocognitive function in order to investigate relationships between the morphology of striatal structures in the executive and motor loops and tests of response inhibition (Stroop test), task switching (Trail Making test part B) and visuomotor function (Trail Making test part A).
Image acquisition
Neuroimaging data were collected on a Philips 3 T Achieva MRI scanner. Conventional MRI sequences (axial T2 multishot turbo field echo) were obtained to detect possible confounding pathology. Volumetric T1-weighted image acquisition used a multishot gradient spin echo pulse sequence with 8.1-ms TR, 3.7-ms TE, 240 × 240 × 234 matrix, 1 mm isotropic voxel size, and an acquisition time of 10 min, 14 s.
Image preprocessing and processing
Surface-based analyses
For the surface-based analyses, each brain volume was corrected for radiofrequency field inhomogeneities
B28 28
and placed into the standard coordinate system of the ICBM-305 average brain volume using a three-translation and three-rotation rigid-body transformation
B29 29
. This procedure corrects for differences in head alignment between subjects to ensure that region of interest measurements are not influenced by different brain orientations between subjects
29
.
The methods for surfaced-based image analysis have been described in detail elsewhere
B30 30
B31 31
B32 32
. Briefly, two investigators blind to exposure status (FFR and LS) devised a detailed manual tracing protocol for the caudate and putamen, which included directions about the order and direction of tracing, numerous visual aids to facilitate the identification of anatomical landmarks, and precise instructions for dealing with scan artifacts. Striatal contours were then manually outlined by the same two investigators on contiguous coronal slices for every subject (Figure
figr fid F1 1). High intra-rater and inter-rater reliabilities (intraclass correlations >0.95) were established based on independent blinded measurement of six scans used in this study. Subsequently, manually derived contours were transformed into 3D parametric surface mesh models with normalized spatial frequency of the surface points within and across brain slices. Each structure was made into a parametric grid containing 100 × 150 grid points or surface nodes. This step ensures precise comparison of anatomy between subjects at each surface point of the structure. A 3D medial curve was computed along the long axis for the surface model of each structure and radial distance measures (distance from the medial core to the surface) were estimated and recorded at each corresponding surface point. These values were used to generate individual distance maps, which were combined to produce correlation maps allowing for visualization of the relationships between striatal morphology and (1) levels of prenatal cocaine exposure, and (2) neuropsychological test scores in exposed participants. In all analyses, quantitative measures of prenatal exposure to tobacco, alcohol, and marijuana were included as nuisance covariates, as well as sex, cube root of total brain volume, and cocaine use by adolescent participants themselves. Since this method estimates radial distance measures, and distance from the medial core to the surface is a 1D measure, cube root of brain volume was used in place of total brain volume (a 3D measure), in order to make the units comparable.
fig Figure 1Region of interest delineationtext
Region of interest delineation. The left and right caudate and putamen were manually delineated on contiguous coronal slices following a detailed protocol devised by the investigators.
graphic file 1866-1955-4-22-1
Volumetric analyses
Preprocessing and definition of cortical and subcortical gray matter regions on structural images were conducted in the UCLA Laboratory of Neuro Imaging (LONI) Pipeline Processing Environment
B33 33
B34 34
B35 35
and using FreeSurfer’s automated brain segmentation software (FreeSurfer 4.0.5,
http://surfer.nmr.mgh.harvard.edu), as described in the work of Fischl and Dale
B36 36
B37 37
B38 38
. We obtained volume measurements of seven subcortical brain regions (thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and ventral diencephalon) as well as six frontal cortical regions (caudal middle frontal cortex, rostral middle frontal cortex, lateral orbitofrontal cortex, medial orbitofrontal cortex, superior frontal cortex, and frontal poles). During preprocessing, high-resolution T1-weighted image acquisitions for each participant were visually inspected for motion artifacts by a trained rater based on a 5-point Likert scale illustrating the severity of motion effects. No participants were rejected due to motion artifacts; however, one subject was rejected due to poor gray -white matter contrast, and another subject was rejected because the raw image data files appeared corrupted. In all remaining participants (n = 40), the T1-weighted images were brain extracted, and gray-white matter boundaries were automatically delineated. All brain extractions were inspected visually and corrected manually as needed.
Volumes for the seven subcortical and six frontal cortical regions of interest, as well as total intracranial volumes were calculated using FreeSurfer’s automatic quantification of cortical and subcortical structures. Procedures are described in detail elsewhere
38
. In summary, a neuroanatomical label was assigned to each voxel in an individual’s structural MRI based on probabilistic information estimated from a manually labeled training set. This manually labeled training set is a result of validated methods from the Center of Morphometric Analysis (
http://www.cma.mgh.harvard.edu). To disambiguate the overlap in intensities between different anatomical structures, FreeSurfer utilized spatial information. Two transformations were performed. First, an optimal linear transformation was carried out by maximizing the likelihood of the native image given a manually labeled atlas. Second, a non-linear transformation was executed on the output of the prior registration step. Finally, a Bayesian parcellation was conducted by using prior spatial information
B39 39
B40 40
. At the end of this processing stream, three probabilities were calculated for each voxel: (1) the probability of the voxel belonging to each of the label classes, based on its location, (2) the neighborhood function, used to determine the likelihood that the voxels belong to a class, based on the classification of neighboring voxels, and (3) the result of the probability distribution function for each voxel based on its intensity.
The accuracy of this technique was shown to be similar to manual methods. The automated segmentations have been found to be statistically indistinguishable from manual labeling
38
. Being completely automated, Freesurfer volume estimates are highly reliable. Nonetheless, in the current study, each brain image was visually inspected for validity of all regions by a single trained blind rater. In over one-third of subjects, the segmentations of the caudate and putamen were judged unsatisfactory, due to pulsation artifacts around the striatum on the high-resolution T1-weighted images. Therefore, the volumes of the caudate and putamen were calculated from the manually derived contours (obtained in the surface-based analyses) for all subjects (n = 40), and these values were used in place of the FreeSurfer outputs in all statistical analyses.
Statistical analyses of demographic, neuropsychological, and volumetric data
Statistical analyses were conducted using SYSTAT 12.0 and SPSS 20.0. Group differences in age, total brain volume, neuropsychological test performance, and prenatal exposure to tobacco, alcohol, and marijuana were evaluated using two-sample independent t-tests. Group differences in gender and postnatal cocaine exposure were assessed with a Pearson Chi-Square Test.
In volumetric analyses, group differences in regional brain volumes were evaluated using separate one-way ANOVA tests for each individual region of interest. In all analyses, prenatal exposure to cocaine was modeled as the independent variable, while the volume (in mm3) of the region of interest was used as the dependent variable. All analyses included the following covariates: prenatal exposure to alcohol, tobacco, and marijuana, in addition to sex, total brain volume, and cocaine use by participants themselves (as measured by a positive hair sample at 10.5 and/or 12.5 years of age). Two-way ANOVAS were subsequently performed in order to examine possible interactions between pre- and postnatal cocaine exposure.
Associations between neuropsychological test scores and levels of prenatal cocaine exposure were investigated with multiple regression analyses using the following equation: Performance = Constant + Level of Prenatal Cocaine Exposure + Prenatal Alcohol Exposure + Prenatal Tobacco Exposure + Prenatal Marijuana Exposure + Sex + Cocaine Use by Participants (as measured by a positive hair sample at 10.5 and/or 12.5 years of age).
Results
Demographics
Demographic descriptors are reported in Table
1. The PCE and CON groups did not differ from each other in age (P = 0.439) but showed a significant difference in gender distribution (P = 0.039), with the exposed group comprising more girls. The two groups significantly differed from each other in prenatal exposure to tobacco (P <0.001) and alcohol (P = 0.011), with the PCE group showing significantly higher levels of exposure to these drugs than participants in the CON group. We also reported a trend-level difference in prenatal exposure to marijuana (P = 0.091) and a significant difference in postnatal exposure to cocaine (P = 0.030) assessed by cocaine-positive hair samples at age 10.5 years and/or 12.5 years. The PCE group tended to have higher levels of prenatal marijuana exposure, and while the CON group comprised an equal number of participants with and without postnatal cocaine exposure, the PCE group included almost twice as many non-users as users. The two groups did not differ in total brain volume (P = 0.846). Nevertheless, in all analyses presented below, total brain volume was used as a covariate along with sex, postnatal cocaine exposure, and prenatal exposure to other drugs of abuse in order to eliminate any variance due to possible disparities in overall brain volume within groups.
Surface-deformation analyses
Main effects of prenatal cocaine exposure
The overall volumes of the caudate and putamen did not significantly differ between participants with prenatal cocaine exposure (the PCE group) and controls (the CON group). In addition, differences in caudate and putamen morphology between these two groups were non-significant after regressing out prenatal exposure to other drugs of abuse, total brain volume, sex, and cocaine use, even when prenatal tobacco exposure was not included as a nuisance covariate. However, 3D surface statistics revealed significant (P <0.05, uncorrected) effects of the amount of prenatal exposure to cocaine on regional patterns of striatal morphology across all participants.
Higher levels of prenatal cocaine exposure were associated with contraction of striatal surfaces in the ventromedial and in the dorsal caudate, and some regions of expansion in the ventrolateral caudate. These effects were stronger in the left caudate (Figures
F2 2.2 and
2.3). Similar but less pronounced results were observed in the right caudate (data not shown).
Figure 22, 3, 4, and 5: Uncorrected surface maps depicting relationships between levels of prenatal cocaine exposure and regional deformations of striatal surface (n = 40)
2, 3, 4, and 5: Uncorrected surface maps depicting relationships between levels of prenatal cocaine exposure and regional deformations of striatal surface (n = 40). Blue-to-light-blue shading indicates regions where higher levels of prenatal cocaine exposure are associated with contraction of striatal surfaces. Red-to-yellow shading displays regions where higher exposure levels are associated with expansion of the surfaces. For all statistical maps, the color bar encodes the uncorrected P values (P <0.05) for the observed effects. 6, 7, 8:Uncorrected surface maps depicting relationships between neuropsychological scores (6: Stroop, 7: Trails A, 8: Trails B) and regional deformations of striatal surface in exposed subjects (n = 28). Red-to-yellow shading displays regions where higher scores (better performance on the Stroop test but longer response times on the Trails test) are correlated with larger regional striatal volumes. Few negative correlations were observed in these analyses. For all statistical maps, the color bar encodes the uncorrected P values (P <0.05) for the observed effects.
1866-1955-4-22-2
Greater prenatal cocaine exposure was associated with contraction of striatal surfaces in the posterior putamen and in the ventrolateral and dorsomedial putamen. Higher levels of prenatal cocaine exposure were associated with large areas of expansion in the anterior putamen, as well as in the dorsolateral and ventromedial putamen. These effects were stronger in the right putamen (Figures
2.4 and
2.5). Similar but less pronounced results were observed in the left putamen (data not shown). Comparable correlational maps in terms of strength and extent were obtained in the left and right caudate and putamen when prenatal tobacco exposure was not included as a nuisance covariate (data not shown). These results did not remain significant after correcting for multiple spatially correlated comparisons using permutation testing.
Neuropsychological correlates of striatal morphology
Following these initial analyses, we examined the two ROIs that showed the most significant effects (left caudate and right putamen), and investigated relationships between neuropsychological test scores and regional deformations of the striatal surface in exposed subjects. Specifically, we first examined correlations between measures of executive functioning and regional deformation of the left caudate surface. Higher scores (better performance) on the Stroop test (Figure
2.6) were associated with larger volume in subregions of the dorsal caudate, while longer response times (lower performance) on part B of the Trail Making test (Figure
2.7) correlated with larger volume in other parts of the dorsal caudate.
We also investigated correlations between a measure of visuomotor functioning and regional deformation of the right putamen surface. Longer response times on part A of the Trail Making test were associated with larger volume of the medial putamen, mostly in the posterior region (Figure
2.8). None of these results remained significant after performing permutation testing in order to correct for multiple spatially correlated comparisons.
Volumetric analyses
In these analyses, we examined group differences in regional brain volumes between the PCE group and the CON group. As in the surface-deformation analyses, in addition to sex, total brain volume, and cocaine use by the participants themselves, we also used prenatal exposure to alcohol, tobacco, and marijuana as nuisance covariates in all analyses in an attempt to detect the specific effects of prenatal cocaine exposure.
Consistent with the surface-based analyses in which we found no significant group differences in overall volumes of the caudate and putamen based on manually-derived contour, here we observed no significant changes in the volume of any subcortical region of interest in the PCE group compared to the CON group in analyses based on automated segmentation. However, we detected group differences in the volumes of some frontal cortical regions.
We observed significant (uncorrected) reductions in regional volumes in the left (P = 0.046) and right (P = 0.036) caudal middle frontal cortices, and in the left lateral orbitofrontal cortex (P = 0.048), in participants with prenatal cocaine exposure compared to controls (Figure
F3 3). On the other hand, in the left (P = 0.072) and right (P = 0.098) frontal poles, we observed trend-level increases in regional brain volumes in the PCE group compared to controls (Figure
3).
Figure 3Group differences in frontal cortical brain volumes (uncorrected results)
Group differences in frontal cortical brain volumes (uncorrected results). Blue and green shading indicates regions where the PCE group showed decreased volumes compared to controls (P <0.05) after controlling for prenatal exposure to tobacco, alcohol, and marijuana as well as sex, total brain volume, and drug use by participants. Red shading indicates regions where the PCE group showed trends for increased volumes compared to controls (P <0.10), using the same covariates. Thicker black contours delineate all of the frontal regions of interest that were examined in these analyses.
1866-1955-4-22-3
We found no significant main effects of postnatal cocaine exposure (cocaine use by participants) on the volume of any frontal cortical region, and there were no significant interactions between pre- and postnatal cocaine exposure. Moreover, neuropsychological performance on the word-color interference Stroop Test, and on parts A and B of the Trail Making Test did not differ significantly between the PCE and control groups (Table
1); and there were no significant correlations between levels of prenatal cocaine exposure and neuropsychological test scores, after co-varying for prenatal exposure to other drugs of abuse, sex, and postnatal cocaine exposure.
Discussion and conclusions
Taken together, these results suggest that prenatal cocaine exposure may lead to regionally specific patterns of morphological changes in the striatum and subtle volumetric differences in certain frontal cortical regions. The most significant finding in our analyses of caudate morphology was an association between levels of prenatal cocaine exposure and surface contraction in the ventromedial and dorsolateral caudate. The ventromedial caudate is part of the lateral orbitofrontal striatal loop, which is involved in the regulation of emotion and social behavior
26
. Interestingly, we also reported regional volume changes in the left lateral orbitofrontal cortex in the PCE group compared to controls. The dorsolateral caudate, on the other hand, is part of the executive loop associated with higher-order cognitive functions
26
, and we also found local volumetric differences in the frontal poles, which play a role in spatial working memory, response inhibition
B41 41
, and the evaluation of self-generated
B42 42
and goal-directed
B43 43
decisions. Therefore, the findings presented here may represent some of the neural correlates of the difficulties in emotional regulation
5
6
and impairments in attention, response inhibition
7
, and visuospatial working memory
B44 44
that have been reported in children with prenatal cocaine exposure.
The putamen is part of the fronto-striatal loop involved in motor control
26
. Most premotor area projections are directed to the medial putamen, and most supplementary motor area projections terminate in the posterior putamen
B45 45
, and in both subregions we found that greater prenatal cocaine exposure was associated with a contraction of striatal surfaces. In addition, we observed significant reductions in regional volumes in the bilateral caudal middle frontal cortices in the PCE group compared to controls, and the caudal part of the middle frontal gyrus corresponds to premotor brain areas. Therefore, it is possible that these findings may be related to the deficits in fine motor coordination that have been reported in this population
10
.
While the direction of changes in striatal surface structure were not predicted a priori, it should be noted that prenatal cocaine exposure was associated with surface contraction in some subregions, and expansion in others. Though the biological mechanisms contributing to these findings remain unclear, the bidirectional nature of regional effects may explain why overall differences in striatal volume were not detected in this study between exposed and control participants in either the surface-based or the volumetric analyses. Similarly, while we did not have specific predictions about the direction of changes in regional frontal cortical volumes, prenatal cocaine exposure was shown to be associated with volume reductions in some frontal subregions, and increased volumes in others. The reasons for this discrepancy remain unclear, but the localized and bidirectional nature of frontal cortical effects may explain in part why certain neuroimaging studies found significant structural differences in the frontal lobes, while others reported negative results.
Consistent with our predictions, we observed very narrowly localized correlations between measures of executive functioning and regional deformation of the dorsal caudate surface. However, the specific areas where this association was significant did not correspond exactly to the subregions of the dorsal caudate where higher levels of prenatal exposure were correlated with greater dysmorphology. The specific areas of the dorsal caudate showing correlations with measures of executive functioning also differed by task: they were more superior and medial for the Stroop test than for part A of the Trail Making test.
As predicted, we also observed a marginally significant correlation between a measure of visuomotor performance and regional deformation of the putamen surface, which was significant in the medial and posterior putamen, where most premotor and supplementary motor area projections terminate
45
, suggesting a possible association between neurological and behavioral abnormalities.
However, while these results suggest that prenatal exposure to cocaine may affect the morphology of the striatum and regional frontal lobe volumes, it is important to keep in mind that the effect sizes were small for all of the results reported here, and that the surface-deformation and volumetric maps were not corrected for multiple spatially correlated comparisons. Nevertheless, the fact that we reported subtle changes consistent with findings from the animal literature and with our a-priori hypotheses, suggests that these differences may be due in part to the specific effects of prenatal cocaine exposure.
We found no association between PCE and neurological test scores, which suggests that brain structure may be a more sensitive biomarker to levels of prenatal cocaine exposure than neuropsychological test performance. This is consistent with findings from the animal literature, suggesting that cognitive tests may be more sensitive to the pattern of maternal consumption than to the amount of cocaine intake, even in the presence of neurobiological alterations
B46 46
. Despite showing evidence for abnormal neuronal migration and cortical lamination as well as neurochemical differences, rhesus monkeys with both ‘high doses’ and ‘low doses’ of PCE do not significantly differ from controls in cognitive performance, whereas monkeys in the ‘escalating dose’ group show impairments
46
.
It should be noted that we did not have data about participants’ use of other drugs, thus we cannot exclude the possibility that postnatal exposure to other substances of abuse may have affected the findings. Another important limitation is that neuroimaging data was available for only 12 adolescent controls. Though we cannot rule out the eventuality that a larger control group would have allowed for the detection of slightly more robust group differences, in the context of the existing literature, these findings support the notion that the effects of PCE on brain structure may be quite subtle. An alternative explanation to findings of modest effects in the current study may be that the marginally significant alterations observed simply reflect relatively minor consequences of PCE on brain development. Some publications suggested that cocaine may be a relatively weak teratogen with few observable neurological or behavioral consequences in humans
B47 47
, unlike other common substances of abuse during pregnancy, which have been more convincingly linked to psychopathology risk, such as alcohol
B48 48
and nicotine
B49 49
.
The small effect sizes observed here as well as regional differences in the direction of effects may help explain why prior investigations of the consequences of prenatal cocaine exposure on brain structure have yielded somewhat conflicting results. Although animal studies of PCE, particularly studies of non-human primates, clearly demonstrate the potential of prenatal cocaine exposure to interfere with brain development at a cellular and biochemical level in various brain regions
24
25
47
B50 50
B51 51
B52 52
, they also suggest that the types and severity of PCE effects largely depend on the route, dose, gestational period, and pattern of consumption
46
. These could be additional contributing factors to the discrepancies in the existing human neuroimaging literature, and to the small effect sizes reported here.
Thus, it is important that future neuroimaging studies of prenatal cocaine exposure with larger samples collect information about adolescent participants’ use of other substances, specific patterns and timing of maternal cocaine consumption, and aim to integrate observations from different brain imaging modalities. This will help determine how structural, metabolic, and functional brain abnormalities resulting from PCE relate to real-life difficulties these children face outside the scanner, as subtle neurological changes may very well be associated with important behavioral, cognitive, or emotional impairments.
Although several promising psychosocial prevention strategies for pregnant women addicted to cocaine have been identified
B53 53
, effective remediation strategies and treatments for prenatally exposed children remain to be developed. The improvement of such strategies will require that we gain a better understanding of the specific, localized and perhaps subtle neurological abnormalities resulting from prenatal cocaine exposure in order to facilitate the translation of research findings to clinical practice.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
FR analyzed and interpreted the data and was the main writer of the manuscript. LS helped with data processing and analysis. TW helped with data collection and data interpretation. KN helped with technical aspects of data analysis and data interpretation. CL helped with data interpretation and helped revise the manuscript. MB helped with data collection and interpretation. FDE helped with data collection and interpretation. ERS was the principal investigator, who supervised the whole project, and helped write the manuscript. All authors read and approved the final manuscript.
bm
ack
Acknowledgments
This work was supported by National Institute of Drug Abuse Grants R21 DA15878 and R01 DA017831 and the March of Dimes (6FY2008-50) awarded to ERS. Additional support was provided by Grants R21 DA027561 awarded to TW and ERS and R01 DA05854 awarded to FDE and MB.
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