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Mapping abnormal subcortical neurodevelopment in a cohort of Thai children with HIV

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Alterations in subcortical brain structures have been reported in adults with HIV and, to a lesser extent, pediatric cohorts. The extent of longitudinal structural abnormalities in children with perinatal HIV infection (PaHIV) remains unclear. We modeled subcortical morphometry from whole brain structural magnetic resonance imaging (1.5 T) scans of 43 Thai children with PaHIV (baseline age = 11.09±2.36 years) and 50 HIV− children (11.26±2.80 years) using volumetric and surface-based shape analyses. The PaHIV sample were randomized to initiate combination antiretroviral treatment (cART) when CD4 counts were 15–24% (immediate: n = 22) or when CD4 < 15% (deferred: n = 21). Follow-up scans were acquired approximately 52 weeks after baseline. Volumetric and shape descriptors capturing local thickness and surface area dilation were defined for the bilateral accumbens, amygdala, putamen, pallidum, thalamus, caudate, and hippocampus. Regression models adjusting for clinical and demographic variables examined between and within group differences in morphometry associated with HIV. We assessed whether baseline CD4 count and cART status or timing associated with brain maturation within the PaHIV group. All models were adjusted for multiple comparisons using the false discovery rate. A pallidal subregion was significantly thinner in children with PaHIV. Regional thickness, surface area, and volume of the pallidum was associated with CD4 count in children with PaHIV. Longitudinal morphometry was not associated with HIV or cART status or timing, however, the trajectory of the left pallidum volume was positively associated with baseline CD4 count. Our findings corroborate reports in adult cohorts demonstrating a high predilection for HIV-mediated abnormalities in the basal ganglia, but suggest the effect of stable PaHIV infection on morphological aspects of brain development may be subtle.
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NeuroImage: Clinical
journal homepage: www.elsevier.com/locate/ynicl
Mapping abnormal subcortical neurodevelopment in a cohort of Thai
children with HIV
Benjamin S.C. Wade
a,b,c
, Victor G. Valcour
d
, Thanyawee Puthanakit
e
, Arvin Saremi
a
,
Boris A. Gutman
f
, Talia M. Nir
a
, Christa Watson
d
, Linda Aurpibul
g
, Pope Kosalaraksa
h
,
Pradthana Ounchanum
i
, Stephen Kerr
e
, Netsiri Dumrongpisutikul
j
, Pannee Visrutaratna
k
,
Jiraporn Srinakarin
l
, Monthana Pothisri
j
, Katherine L. Narr
b
, Paul M. Thompson
a
,
Jintanat Ananworanich
e,m,n,o
, Robert H. Paul
c
, Neda Jahanshad
a,
, on behalf of the PREDICT and
Resilience Study Groups
a
Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA,
USA
b
Ahmanson-Lovelace Brain Mapping Center University of California, Los Angeles, Los Angeles, CA, USA
c
Missouri Institute of Mental Health, University of Missouri St. Louis, St. Louis, USA
d
Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA
e
HIV-NAT, the Thai Red Cross AIDS Research Centre, Bangkok, Thailand
f
Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA
g
RIHES, Chiang Mai University, Chiang Mai, Thailand
h
Department of Pediatrics, Khon Kaen University, Khon Kaen, Thailand
i
Chiang Rai Prachanukroh Hospital, Chiang Rai, Thailand
j
Department of Radiology, Chulalongkorn University Medical Center, Bangkok, Thailand
k
Department of Radiology, Chiang Mai University, Chiang Mai, Thailand
l
Department of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
m
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, MD, USA
n
Department of Global Health, University of Amsterdam, Amsterdam, the Netherlands
o
Henry M. Jackson Foundation for the Advancement of Military Medicine, MD, USA
ARTICLE INFO
Keywords:
Neuro HIV
Pediatric HIV
Brain development
Subcortical shape analysis
MRI
ABSTRACT
Alterations in subcortical brain structures have been reported in adults with HIV and, to a lesser extent, pediatric
cohorts. The extent of longitudinal structural abnormalities in children with perinatal HIV infection (PaHIV) remains
unclear. We modeled subcortical morphometry from whole brain structural magnetic resonance imaging (1.5 T) scans
of 43 Thai children with PaHIV (baseline age = 11.09 ± 2.36 years) and 50 HIV− children (11.26 ± 2.80 years)
using volumetric and surface-based shape analyses. The PaHIV sample were randomized to initiate combination
antiretroviral treatment (cART) when CD4 counts were 15–24% (immediate: n= 22) or when CD4 < 15% (deferred:
n= 21). Follow-up scans were acquired approximately 52 weeks after baseline. Volumetric and shape descriptors
capturing local thickness and surface area dilation were defined for the bilateral accumbens, amygdala, putamen,
pallidum, thalamus, caudate, and hippocampus. Regression models adjusting for clinical and demographic variables
examined between and within group differences in morphometry associated with HIV. We assessed whether baseline
CD4 count and cART status or timing associated with brain maturation within the PaHIV group. All models were
adjusted for multiple comparisons using the false discovery rate. A pallidal subregion was significantly thinner in
children with PaHIV. Regional thickness, surface area, and volume of the pallidum was associated with CD4 count in
children with PaHIV. Longitudinal morphometry was not associated with HIV or cART status or timing, however, the
trajectory of the left pallidum volume was positively associated with baseline CD4 count. Our findings corroborate
reports in adult cohorts demonstrating a high predilection for HIV-mediated abnormalities in the basal ganglia, but
suggest the effect of stable PaHIV infection on morphological aspects of brain development may be subtle.
https://doi.org/10.1016/j.nicl.2019.101810
Received 5 January 2019; Received in revised form 25 March 2019; Accepted 1 April 2019
Corresponding author at: Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, University of Southern California, 4676 Admiralty Way,
Marina del Rey, CA 90292, USA.
E-mail address: neda.jahanshad@usc.edu (N. Jahanshad).
NeuroImage: Clinical 23 (2019) 101810
Available online 02 April 2019
2213-1582/ © 2019 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
T
1. Introduction
Long-term survival and quality of life of children perinatally in-
fected with HIV has improved dramatically with better access to com-
bination antiretroviral therapy (cART). Pediatric HIV-related en-
cephalopathy has decreased in the cART era (Patel et al., 2009;Raskino
et al., 1999;Shanbhag et al., 2005), down to 1.6% from a prevalence of
76% prior to cART (Chiriboga et al., 2005;Cooper et al., 1998), greatly
extending life expectancy. However, as the number of chronically-in-
fected children living with HIV increases, there is a need to understand
the impact of the infection on brain development. HIV is associated
with cognitive and motor impairments in adults (Brew, 2004;Heaton
et al., 1995;Sacktor et al., 2002) and children (Paul et al., 2018;Van
Rie et al., 2008). In adults, these impairments are commonly associated
with disruption to frontal subcortical circuitry, though recent studies
indicate more diffuse effects in chronically infected individuals (Baker
et al., 2017;George et al., 2009;Safriel et al., 2000).
Few studies have examined neuroimaging abnormalities in pediatric
HIV. Work by Herting and colleagues (Herting et al., 2015) identified
associations between HIV severity, peak viral RNA levels and nadir
CD4%, and the functional connectivity of the default mode network
(DMN). Interestingly, disease severity was related to both increased and
decreased BOLD signal correlations both within and between DMN
connectivity. These patterns of connectivity were also predictive of
processing speed. The authors suggest that these findings may reflect a
global reorganization of the DMN and underlie many of the cognitive
dysfunctions found in youth with HIV.
Studies of microstructural brain integrity using diffusion tensor
imaging reveal lower whole brain fractional anisotropy in HIV+ youths
(Hoare et al., 2018;Uban et al., 2015), and increased mean and axial
diffusivity with higher viral RNA load in plasma (Hoare et al., 2015).
Macrostructural neuroimaging studies have yielded more equivocal
results. Cohen et al. reported more severe white matter hyperintensities
and lower gray and white matter volumes in HIV+ children age 8–18
compared to HIV-uninfected controls (Cohen et al., 2016). Hoare and
colleagues reported decreased cerebral gray matter volumes, cortical
surface area, and decreased gyrification among 204 adolescence with
paHIV between the ages of 9 to 11 years relative to 44 age-matched
controls (Hoare et al., 2018). Sarma and colleagues reported lower
volumes of the posterior corpus callosum and external capsule, but
increased volumes of multiple cortical and subcortical gray matter re-
gions (Sarma et al., 2014). Recent work by our group to clarify the
discrepancies in gray matter volumes in pediatric HIV revealed larger
volumes of the caudate, accumbens, and cortical gray matter in HIV+
children under age 12, with no differences in volumes among older
children (Paul et al., 2018b).
Volumetric estimates of relatively large subcortical regions, how-
ever, are not sensitive to potentially subtle disease-related structural
deformations in subsections or subfields of the structures that may
better represent specific cell types. One means of modeling these more
specific abnormalities is to use high-dimensional surface-based shape
descriptors on the extracted subcortical region of interest. We have
demonstrated that these shape features are highly sensitive to focal
abnormalities when compared to volumetric measures in HIV+ older
adults (Wade et al., 2015), as well as other patient populations (e.g.,
traumatic brain injury; (Tate et al., 2016;Tate et al., 2018) treatment-
resistant depression (Wade et al., 2016;Wade et al., 2017).
To date, only one study has used shape analysis to characterize local
subcortical deformations in youth with HIV. Lewis-de los Angeles and
colleagues applied multiatlas FreeSurfer-initiated large-deformation
diffeomorphic metric mapping (Khan et al., 2008) to identify sub-
cortical shape deformations related to peak HIV viral load and nadir
CD4% in PHACS, a cohort of 40 youth from the United States, all with
perinatally acquired HIV (PaHIV). The group found deformations of the
thalamus, caudate, pallidum, and putamen related to peak HIV RNA
counts. Most deformations were inwards, although outward
deformations were also detected; these outward deformations, local
volumetric expansion, of the medial and posterior thalamus were
identified in association with higher nadir CD4%. Further, shape var-
iations in the caudate and thalamus were associated with cognitive
impairments (Lewis-de Los Angeles et al., 2016).
Nearly all of these previous studies were limited by their cross
sectional designs, and many did not compare the HIV+ individuals to
matched controls. In this study we investigated whether HIV status
associated with cross sectional or longitudinal structural deformations
in seven subcortical brain regions in a relatively homogeneous sample
of 43 youth with HIV compared to 50 uninfected controls, all from three
scanning sites across Thailand. Participants (age 6 to 16) were enrolled
in a longitudinal study to examine outcomes associated with early
versus deferred initiation of cART (ClinicalTrials.gov, number
NCT00234091; (Puthanakit et al., 2012)). Both adult and adolescent
HIV literature suggest a disproportionate effect of HIV status on sub-
cortical brain structures (Fennema-Notestine et al., 2013;Jernigan
et al., 2011), particularly the basal ganglia (Ances et al., 2012;Li et al.,
2018;Wade et al., 2015). Given this and the need to restrict the number
of statistical comparisons, we focused our analyses on prominent sub-
cortical regions of interest. We hypothesized that children with HIV
would exhibit significant deformations in select brain regions, with
reduced local and global volumetric distortions. Within the HIV+
subset, we further evaluated the effect of current CD4 count, and cART
treatment status or timing (early versus deferred initiation), on sub-
cortical morphometry; we hypothesized that higher CD4 count would
show patterns more similar to HIV− controls while cART treatment
status would not show any effects.
2. Methods
2.1. Participants
The sample included 43 HIV+ (baseline age = 11.09 ± 2.36; 20
female; 32 on cART; 21 deferred cART) and 50 HIV− (baseline
age = 11.26 ± 2.80; 29 female) Thai participants enrolled in the
Pediatric Randomized Early versus Deferred Initiation in Cambodia and
Thailand (PREDICT) clinical trial (ClinicalTrials.gov, number
NCT00234091; (Puthanakit et al., 2013;Puthanakit et al., 2012).
Baseline demographic and clinical characteristics of the groups are
provided in Table 1. Enrollment into the PREDICT trial occurred be-
tween 2005 and 2007, resulting in 150 children randomized to the
immediate arm, 150 randomized to the deferred arm. Two control
samples were recruited, including 164 healthy unexposed uninfected
(HUU) and 155 HIV-exposed but uninfected children (HEU)
(Puthanakit et al., 2013). A neuro-focused substudy was initiated after
the start of the main PREDICT trial, which included neuroimaging and
neuropsychological assessment. This study includes HIV+, HEU, and
HUU children who completed the neurosubstudy. For this imaging
analysis, all participants met the following inclusion criteria: (1)
age < 18 years, (2) able to tolerate MRI, and (3) written informed
consent signed by a caregiver and assent for participants 6 to 17 years
of age. Exclusion criteria included prior or current brain infection,
neurological or psychiatric disorder, any congenital abnormality or
head injury with a loss of consciousness. The Institutional Review
Boards (IRBs) of each study site approved the study.
2.2. Image acquisition
Participants underwent repeat structural magnetic resonance ima-
ging (MRI) with an average of 52 weeks between baseline and follow-up
scans (median = 52.7 weeks; range = 39.2 to 116.7). Whole brain
structural T1-weighted MRI was performed on GE 1.5 T scanners at all
study sites using the following protocol: axial plane, 3D SPGR images
with a minimum TE at full echo, TR = 11.2 ms, slice thick-
ness = 1.0 mm, isotropic voxel size; 256 × 256 imaging matrix. The
B.S.C. Wade, et al. NeuroImage: Clinical 23 (2019) 101810
2
number of slices acquired were between 130 and 170, and varied per
scan to ensure full head coverage. Quality assurance of the MRI ac-
quisitions was performed throughout the study using a human phantom
to ensure consistent scaling. Motion was assessed in real-time by the
technician. The scan was repeated for any participant for whom motion
artifacts were detected. All participants with longitudinal MRIs used for
this analysis had at least one scan without detectable motion at each
time point. Therefore, motion was not a significant issue at the image
processing stage, and no data points were excluded after the data col-
lection was completed. Two of the authors (N.J. and B.W.) reviewed all
subject's FLAIR images to screen for white matter hyperintensities
(WMH) that might compromise regional FreeSurfer segmentations. No
concerning WMHs were identified in scans of participants that had
originally passed quality control, thus there was no need to exclude
more data on this basis.
2.3. Morphological descriptors
FreeSurfer version 5.3 (Fischl et al., 2002) was used to remove non-
brain tissue, normalize intensities, and conducted semiautomated vo-
lumetric parcellation using probabilistic information from manually
labeled training sets. FreeSurfer's default cross-sectional workflow was
applied to each scan. Seven subcortical brain regions of interest (ROI)
were selected: the thalamus, putamen, pallidum, amygdala, accumbens,
caudate, and hippocampus. Segmentations were completed for each
hemisphere with visual quality inspection completed using ENIGMA
protocols: http://enigma.usc.edu/protocols/imaging-protocols/ to en-
sure their quality.
To define shape descriptors on the subcortical surfaces, a 3D co-
ordinate mesh was applied to the outer surface of each ROI. The
parameterization of each surface was obtained using the medial
“Demons” framework detailed in (Gutman et al., 2015;Gutman et al.,
2012). Briefly, each surface was conformally mapped to the spherical
domain and rigidly rotated to a probabilistic atlas. Each segmentation
was warped to a spherical template using Spherical Demons (Gutman
et al., 2013) on the basis of curvature to define the local thickness of the
surface with respect to a skeletonization or the surface “medial core.”
The medial core and surface-based curvature were mapped to each
surface to render two measures at each point along the surface: (1) the
radial distance (RD), a proxy for the local thickness, and (2) the log of
the Jacobian determinant (JD) which indicates regional surface area
expansion or contraction. For example, if the anterior hippocampus
were significantly thinner in a group of elderly patients with Alzhei-
mer's disease compared to age-matched controls, the RD value would be
smaller in the anterior hippocampus of the Alzheimer's patients. If in-
stead the healthy cohort hippocampi did not differ from the Alzheimer's
group on the basis of local thickness but was relatively elongated, the
log-JD would be positive for the healthy group but negative for the
Alzheimer's group, on average. We note that a shorter, yet thicker re-
gion, may not show a difference in volume, yet the shape characteristics
defined here would help identify these trends. A total of 27,120 vertices
were assessed across the fourteen (seven left and right) selected ROIs.
2.4. Statistical methods
Fixed effects multivariate linear regression analyses were used to
model associations between the subcortical shape features (RD and JD)
or volume and HIV-related factors at baseline and over time. HIV status
represented the main effect of interest tested across all vertices (mod-
eled categorically). We covaried for age, sex, total estimated in-
tracranial volume, measures of socioeconomic status, including edu-
cation level of the caregiver (modeled categorically: greater than
elementary school level or not) and their income level (modeled cate-
gorically: average, above average, or below average). As scans were
collected across three institutions across Thailand, we also adjusted for
scan site (modeled categorically; 3 sites) in all models. Within the HIV
+ group, we separately assessed the effects of baseline CD4 t-cell count
(modeled continuously), cART status (modeled categorically), and
cART timing (modeled categorically as deferred versus immediate in-
itiation) keeping the same covariates as before.
Longitudinal models assessed the relationship between HIV status
and the change in the morphometry over time. Difference scores for
both RD and JD were defined as morphometry
follow-up
– morphome-
try
baseline
, and longitudinal models included an additional covariate to
model the time between the scans (in days).
Some variables had missing information: caregiver income level
(N= 8) and education level (N= 1). We therefore ran two models. In
the first, the subjects with missing data were not included in the
models, and the second, the missing values for these data were imputed
according to the overall mode of the sample: for patient income this was
average and elementary school or below for education.
All models were adjusted for multiple comparisons across vertices
for shape measures and across structures for volume measures using the
standard false discovery rate (FDR) method with a false-positive rate of
5% (q= 0.05) (Benjamini and Hochberg, 1995). FDR adjustments were
applied within the family of all tests performed on a single surface
correcting for separate tests within each surface. We further required
that a minimum of three adjacent vertices show a significant association
with the main effect, after adjustment for vertex wise multiple com-
parisons, to be considered a viable association; this further reduces the
likelihood of false positives. Volumetric models were adjusted using
FDR applied to the whole set of ROIs tested.
3. Results
3.1. Demographics
HIV+ and HIV− participants did not differ significantly by age
(Welch t= −0.31, df = 90.96, p= .75) or sex (χ
2
=0.80, df = 1,
p= .36). Baseline CD4 counts differed significantly by HIV status
(mean HIV− = 954 per μl, sd = 299.81; mean HIV+ = 727 per μl,
sd = 325.29; Welch t= −3.46, df = 86.30, p≤ .001). Days to follow-
up differed significantly between groups (Welch t= 4.84, df = 48.85,
p< .0001) with the average days to follow-up for HIV− being 364.44
(sd = 42.97) and HIV+ being 472.69 (sd = 140.84). There were no
significant differences in age, sex or days to follow-up between cART-
positive (cART+) and cART-negative (cART-) HIV+ participants.
Baseline CD4 counts differed significantly by cART status (mean
cART+ = 853.53 per μl, sd = 270.80, mean cART- = 362.54 per μl,
sd = 140.49; Welch t= 7.68, df = 33.97, p< .00001).
Table 1
Demographic and clinical characteristics.
HIV+ (n= 43) HIV− (n= 50)
Age, mean (sd), y 11.09 (2.36) 11.26 (2.80)
Sex, M/F 23/20 29/21
cART status, Y/N 32/11
Age of cART initiation, mean (sd), y
a
9.39 (3.23)
Log Viral RNA count, mean (sd), copies/ml 9.85 (11.16)
Detectable/undetectable vRNA, (%)
b
25/75 –
CD4 count, mean (sd), cells/mL
c
728 (323) 954 (299)
HEU/HUU – 25/25
Site, Chula/CM/KKU 15/25/3 20/29/0
Income, above average/average/below
average
1/14/20 8/24/18
Education, high school or greater/up to
elementary school
18/25 23/26
Days to follow-up
c
472.69
(140.84)
364.44 (42.97)
a
Based on the date that a participant received the first drug in the cART
cocktail.
b
Undetectable vRNA levels are < 50 copies per mLl.
c
Significant difference.
B.S.C. Wade, et al. NeuroImage: Clinical 23 (2019) 101810
3
3.2. HIV status
The thickness (RD) of the right medial inferior pallidum was sig-
nificantly lower in the HIV+ group, relative to controls by approxi-
mately 4%. The area of this shape deformation covered 0.06% of the
right pallidum surface (8 adjacent vertices; mean t-value = −4.002;
mean p-value < .001) is illustrated in Fig. 1. The extent of this sig-
nificant association was only moderately increased when income was
not included as a covariate (see Supplementary Fig. 1) but was elimi-
nated when subjects with missing income values were excluded (i.e.,
when we did not impute their values). No volumetric associations with
HIV status were found at baseline. No longitudinal differences in shape
or volume measures were associated with HIV status.
To confirm that shape and volume measures associated with de-
velopment, we evaluated the effect of age in the same regression models
in which HIV status was the main effect. We observed widespread as-
sociations between RD, JD, and volume measures with age across all
subcortical regions at baseline; only a minority of regions exhibited
longitudinal volumetric associations with age.
Similarly, we evaluated shape and volume associations with income
and education levels to determine if these socioeconomic measures
confer a larger effect on morphometry than HIV status. At baseline, no
associations were found with education level, however, the volume of
the bilateral putamen and JD of the right putamen (~8% of the total
surface) was significantly reduced in subjects with an average income
relative to those with above average income. An important caveat,
though, is that there were only n= 9 participants in the above-average-
income category. No longitudinal associations with socioeconomic or
demographic measures were observed longitudinally.
3.3. Baseline CD4 count and treatment status within HIV+ adolescents
Baseline CD4 count was significantly associated with RD across 43%
of the total surface of the left pallidum (mean t-value = −3.0; mean p-
value < .01); see Fig. 2 (a-b). Similarly, baseline CD4 count was sig-
nificantly associated with JD across 34% of the surface of the left pal-
lidum (mean t-value = −3.0; mean p-value < .01); see Fig. 2 (c-d). The
distribution of significant associations with CD4 count were similar
when we did not covary for income level (see Supplementary Fig. 2).
When the eight PaHIV participants with missing covariate information
(specifically missing family income) were excluded the extent of the
significant association with CD4 count was greatly reduced in the left
pallidum and additional regional associations in the right caudate and
bilateral amygdala were identified (see Supplementary Fig. 3). The total
volume of the left pallidum was also significantly and negatively as-
sociated with baseline CD4 count (t= −3.42; p< .05; b = −0.42);
see Fig. 3(a). The significance of this association remained when in-
come was not included as a covariate but did not survive when parti-
cipants with missing income data were excluded. All significant asso-
ciations were such that participants with higher CD4 counts had smaller
RD, JD, and volume measures, on average. Baseline CD4 count was
significantly associated with the trajectory of the left pallidal volume
(t= 3.32; p < .05; b = 0.25) but not shape; children with higher CD4
counts had increased rates of left pallidum volume growth compared to
those with lower CD4 counts (see Fig. 3(b)). This significant long-
itudinal association, however, did not survive multiple comparisons
correction when four potential outliers in the volumetric range flagged
by the interquartile range rule were excluded (p> .1). As hypothe-
sized, neither cART status nor cART timing were significantly asso-
ciated with baseline or longitudinal shape or volume among the parti-
cipants with HIV.
4. Discussion
In this study we observed a strong association between CD4 t-cell
count and regional morphometry of the left pallidum among adoles-
cence with HIV. Specifically, those with higher CD4 counts had reduced
thickness and surface area of pallidal subregions and total pallidal vo-
lume. Nevertheless, longitudinally, the left pallidum total volume in-
creased significantly more among children with higher baseline CD4
counts. We further observed that adolescence with HIV had only
minimal morphological differences compared to uninfected controls at
baseline; income level was seemingly more associated with subcortical
shape and volume than HIV status. Nevertheless, a medial inferior re-
gion of the right pallidum was thinner in adolescence with HIV com-
pared to controls. Longitudinal volumetric differences were associated
with baseline CD4 count; however, no longitudinal shape or volume
differences were associated with HIV or cART status.
The basal ganglia has been shown to be highly affected in HIV
(Aylward et al., 1993;Berger and Arendt, 2000;Berger and Nath, 1997;
Wright et al., 2016). The predilection for the basal ganglia may be
mediated through a mutli-deterministic model including weak tight
junctions between astrocytic feet comprising the blood brain barrier,
high concentration of CCR5 chemokine receptors, and susceptibility to
oxidative stress. Previous work by our group showed that the pallidum's
volume is significantly reduced in elderly patients with HIV.
Fig. 1. Subcortical shape differences in the right pallidum between HIV+ and HIV− participants. (a) T-value map highlighting region of significantly different local
thickness (RD value) associated with HIV status. (b) Boxplots of average local thickness in vertices identified as significantly different in (a).
B.S.C. Wade, et al. NeuroImage: Clinical 23 (2019) 101810
4
Interestingly, this same study identified a trend-level increase in the
local volume of the anterior right pallidum associated with extended
time since diagnosis (Wade et al., 2015). Lewis-de Los Angeles et al.
also observed shape variations, both local volumetric dilations and re-
ductions, of the pallidum and putamen associated with HIV severity (as
captured by peak HIV RNA load) (Lewis-de Los Angeles et al., 2016).
Our finding suggests that on average, adolescents with higher baseline
CD4 counts have lower regional thickness, surface area, and total vo-
lume.
While in most cases, larger or thicker neuroimaging derived sub-
cortical regions are considered to be associated with healthier brains,
this is not always the case, particularly for the pallidum. For example,
Turner and colleagues reported significantly larger pallidum volumes in
people with autism spectrum disorder (ASD) based on a sample of 472
ASD and 538 non-ASD controls between the ages of 6–64 years (Turner
et al., 2016). Jørgensen et al. also reported an increased volume of the
pallidum among 82 patients with long-term treated schizophrenia re-
lative to 106 healthy controls (Jorgensen et al., 2016). Enlarged pal-
lidum volumes in schizophrenia was also reported in a much larger
study by van Erp and the ENIGMA consortium who reported an in-
creased pallidum volume in a meta-analysis of 2028 patients with
schizophrenia and 2540 controls (van Erp et al., 2016).
More directly related to our current study, Randall et al. in-
vestigated abnormalities in subcortical gray matter volumes in 43 HIV
+ and 18 HIV− 5-year old Xhosa children who were initiated to ART
before 18 months of age; 27 initiated ART before 12 weeks of age and
Fig. 2. Left pallidum shape (RD top and JD bottom) associations with CD4 count within HIV+ participants. T-value maps highlighting clusters of vertices where
shape is significantly associated with CD4 count; all were inversely associated (a & c). Figures b & d are scatterplots showing the average RD or JD values within
significant regions plotted against participant CD4 count.
B.S.C. Wade, et al. NeuroImage: Clinical 23 (2019) 101810
5
16 initiated after 12 weeks. The group reported that HIV+ children had
larger left pallidum volumes compared to the uninfected group and that
this difference was largely driven by children initiated to ART after
12 weeks of age (Randall et al., 2017). The authors suggest that larger
differences in the later-initiated group is evidence neuroprotective ef-
fects of earlier treatment. Our analysis of cART timing and status,
however, did not identify significant associations with brain morpho-
metry. This is possibly due to two factors: The number of children in
this sample who did not undergo cART was very small thus limiting the
power of between-group analyses. Additionally, children were selected
for the parent study due to ability to survive without cART at the time
of randomization. Thus, survivor tendencies may mitigate our ability to
detect direct associations with cART and its benefits.
The absence of cART-related findings in this cohort squared with
our expectations for several reasons. Children in the parent study were
treatment-naive at the time of enrollment. The participants were then
randomly assigned to begin cART when CD4 < 15% or when
CD4 < 25% deferred or immediate treatment arms. Thus, only some of
the original deferred group would not be on cART at baseline. Further,
as only 11 children were untreated at baseline, we anticipated that this
sample was underpowered to resolve treatment effects.
Though speculative, it is possible that the observed inverse corre-
lation between CD4 count and left pallidal volume reflects ongoing
disease mechanisms among individuals with low CD4 cell count; but,
further studies directly assessing markers of inflammation are needed to
test this hypothesis. Further, higher baseline CD4 counts were sig-
nificantly associated with increased subsequent growth of the left pal-
lidum's total volume which suggests that pallidal growth is increased in
healthier adolescence.
HIV-associated cognitive impairment is an important topic of in-
vestigation and has been widely reported in a number of previous
studies (Brew, 2004;Sacktor et al., 2002;Van Rie et al., 2008). We did
not explore associations between cognition and brain morphometry in
this study, however, as a prior study of this same cohort described
cognitive abnormalities in paHIV and reported minimal disease-related
cognitive changes (Paul et al., 2018). As such, the present study was
conducted to investigate brain integrity longitudinally in paHIV using
an innovative and sensitive analysis of parenchymal morphology.
Several notable limitations should be considered in interpreting
these findings. First, the one-year time frame between baseline and
follow-up scans may not have been sufficient to observe important
changes. The average baseline age of our participants was 11 years and
ranged from 6 to 16 across diagnostic groups, an age span characterized
by complex patterns of age and sex-dependent rates of gray matter
pruning and myelination (Giedd, 2004). Given this, a wider time frame
and future follow-up imaging sessions would be beneficial. However,
numerous baseline and longitudinal abnormalities among the HIV+
cohort were identified. We additionally note that the time to follow-up
was significantly longer in the HIV+ cohort. While this cannot be
completely corrected, we included time to follow-up as a covariate in
our longitudinal models. As discussed previously, the original sample
included three time points, however, the HIV+ cohort was a year older
at baseline relative to the control group and it is possible that the use of
different baseline time points across the two groups introduced a sys-
tematic bias in our models. Another limitation for this study was that
certain data points, primarily for income level, required imputation.
While this is an inherent limitation, we observed only minor differences
in the distribution of significant associations between models that in-
cluded or excluded income levels (see Supplementary Figures).
In conclusion, we observed shape abnormalities among HIV+
children at first scan, which attenuated in magnitude over the course of
12 months as longitudinal subcortical abnormalities were non-sig-
nificant. The most robust HIV-related effects were instead shape and
volumetric associations with CD4 cell count within the pallidum of
paHIV children. Although more work needs to be done to disentangle
potential effects of neuroinflammatory processes, this approach has not
previously been applied to identify abnormalities in longitudinal ima-
ging profiles of children with paHIV. Taken together, our findings
suggest that the effects of treated HIV on the morphometry of sub-
cortical structures in adolescence is somewhat minor.
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.nicl.2019.101810.
200 400 600 800 1000 1200 1400
−200 0 200 400 600
200 400 600 800 1000 1200 1400
1000 1500 2000 2500
Baseline CD4 Count
Left Pallidum Volume mm3: Baseline
Baseline CD4 Count
Left Pallidum Volume Change mm3: Follow-u p - Baseline
(a) (b)
Fig. 3. Scatterplots highlighting the significant associations between baseline CD4 counts and (a) baseline left pallidum volume and (b) the change in left pallidum
volume between baseline and follow-up time points. In b, red points indicate four subjects that are potentially outliers in terms of volumetric change as flagged by the
interquartile range rule. The red dashed regression line is fit to the set of subjects excluding the potential outliers.
B.S.C. Wade, et al. NeuroImage: Clinical 23 (2019) 101810
6
Conflict of interest
JA has received honorarium for advisory meetings participation
from Merck, ViiV Healthcare and Tetralogic. PMT and NJ have research
related grant support from BioGen Inc., unrelated to the contents of this
manuscript. Other authors have no disclosures related to the study.
Acknowledgements
This work was supported by R01MH089722 (V. Valcour) and
R01MH102151 (T. Puthanakit and J. Ananworanich) and also in part
by NIH ‘Big Data to Knowledge’ (BD2K) Center of Excellence grant
U54EB020403, P41EB015922, R01AG059874, R01MH117601, NIH
Institutional Training Grant T32AG058507, the National Science
Foundation Graduate Research Fellowship under Grant No. DGE-
0707424 (BW) and by a NARSAD Young Investigator Grant from the
Brain & Behavior Research Foundation (27786; BW). The main rando-
mized study was supported by a grant from the National Institute of
Allergy and Infectious Diseases of the US National Institutes of Health
through the Comprehensive International Program of Research on AIDS
Network (U19 AI53741), and was co-funded by the Eunice Shriver
Kennedy National Institute of Child Health and Human Development
and the National Institute of Mental Health, the National Research
Council of Thailand, and National Health Security Office, Thailand.
Antiretroviral drugs were provided by ViiV Healthcare,
GlaxoSmithKline, Boehringer Ingelheim, Merck, Abbott, and Roche.
The views expressed are those of the authors and should not be con-
strued to represent the positions of the U.S. Army, the Department of
Defense, the National Science Foundation, the National Institutes of
Health or US Department of Health and Human Services.
We would also like to acknowledge the PREDICT study group con-
sisting of the following:
HIV Netherlands Australia Thailand (HIV-NAT) Research
Collaboration, Thai Red Cross AIDS Research Center, Bangkok,
Thailand; Dr.Kiat Ruxrungtham, Dr.Jintanat Ananworanich,
Dr.Thanyawee Puthanakit, Dr.Chitsanu Pancharoen, Dr.Torsak
Bunupuradah, Dr.Wasana Prasitsuebsai, Stephen Kerr, Sasiwimol
Ubolyam, Apicha Mahanontharit, Tulathip Suwanlerk, Jintana Intasan,
Kanchana Pruksakaew, Chulalak Sriheara, Tanakorn Apornpong,
Jiratchaya Sophonphan, Ormrudee Rit-im, Wanchai Thongsee, Orathai
Chaiya, Kesdao Nantapisan, Umpaporn Methanggool, Dr.Sukalaya
Lerdlum, Mantana Pothisri Bamrasnaradura Infectious Diseases
Institute, Nonthaburi,Thailand; Dr.Jurai Wongsawat, Supeda
Thongyen, Piyawadee Chathaisong, Vilaiwan Prommool, Duangmanee
Suwannamass, Simakan Waradejwinyoo, Nareopak Boonyarittipat,
Thaniya Chiewcharn,Sirirat Likanonsakul, Chatiya Athichathana,
Boonchuay Eampokalap, Wattana Sanchiem. Srinagarind Hospital,
Khon Kaen University, Khon Kaen, Thailand; Dr.Pope Kosalaraksa,
Dr.Pagakrong Lumbiganon, Piangjit Tharnprisan, Chanasda Sopharak,
Viraphong Lulitanond, Samrit Khahmahpahte, Ratthanant Kaewmart,
Prajuab Chaimanee, Mathurot Sala, Thaniita Udompanit, Ratchadaporn
Wisai, Somjai Rattanamanee, Yingrit Chantarasuk, Sompong
Sarvok,Yotsombat Changtrakun,Soontorn Kunhasura, Sudthanom
Kamollert, Petcharakorn Hanpanich, Wuttisak Boonphongsathian.
Queen Savang Vadhana Memorial Hospital, Chonburi, Thailand;
Dr.Wicharn Luesomboon, Isara Limpet-ngam, Daovadee Naraporn,
Pornpen Mathajittiphun, Chatchadha Sirimaskul, Woranun Klaihong,
Pipat Sittisak, Tippawan Wongwian, Kansiri Charoenthammachoke,
Pornchai Yodpo. Nakornping Hospital, Chiang Mai, Thailand;
Dr.Suparat Kanjanavanit, Thida Namwong, Duangrat Chutima, Suchitra
Tangmankhongworakun,Pacharaporn Yingyong, Juree Kasinrerk,
Montanee Raksasang,Pimporn Kongdong,Siripim Khampangkome,
Suphanphilat Thong-Ngao, Sangwan Paengta, Kasinee Junsom, Ruttana
Khuankaew, Parichat Moolsombat, Duanpen Khuttiwung, Chanannat
Chanrin. Chiangrai Regional Hopsital, ChiangRai, Thailand; Dr.
Rawiwan Hansudewechakul, Dr. Yaowalak Jariyapongpaiboon, Dr.
Chulapong Chanta, Areerat Khonponoi, Chaniporn Yodsuwan, Warunee
Srisuk, Pojjavitt Ussawawuthipong, Yupawan Thaweesombat, Polawat
Tongsuk, Chaiporn Kumluang, Ruengrit Jinasen, Noodchanee
Maneerat, Kajorndej Surapanichadul, Pornpinit Donkaew.
PrapokklaoHospital, Chantaburi, Thailand; Dr. Chaiwat Ngampiyaskul,
Wanna Chamjamrat, Sayamol Wattanayothin, Pornphan Prasertphan,
Tanyamon Wongcheeree, Pisut Greetanukroh, Chataporn
Imubumroong, Pathanee Teirsonsern. Research Institute for Health
Sciences, Chiang Mai University, Chiang Mai, Thailand; Dr. Virat
Sirisanthana, Dr. Linda Aurpibul, Dr. Pannee Visrutaratna, Siriporn
Taphey, Tawalchaya Cholecharoentanan, Nongyow Wongnum,
Chintana Khamrong, Rassamee Kaewvichit, Kittipong
Rungroengthanakit.
References
Ances, B.M., Ortega, M., Vaida, F., Heaps, J., Paul, R., 2012. Independent effects of HIV,
aging, and HAART on brain volumetric measures. J. Acquir. Immune Defic. Syndr.
59, 469–477.
Aylward, E.H., Henderer, J.D., McArthur, J.C., Brettschneider, P.D., Harris, G.J., Barta,
P.E., Pearlson, G.D., 1993. Reduced basal ganglia volume in HIV-1-associated de-
mentia: results from quantitative neuroimaging. Neurology 43, 2099–2104.
Baker, L.M., Cooley, S.A., Cabeen, R.P., Laidlaw, D.H., Joska, J.A., Hoare, J., Stein, D.J.,
Heaps-Woodruff, J.M., Salminen, L.E., Paul, R.H., 2017. Topological organization of
whole-brain white matter in HIV infection. Brain Connect. 7, 115–122.
Benjamini, Y., Hochberg, Y., 1995. Controlling the false discovery rate - a practical and
powerful approach to multiple testing. J. R. Stat. Soc. B Methodol. 57, 289–300.
Berger, J.R., Arendt, G., 2000. HIV dementia: the role of the basal ganglia and dopami-
nergic systems. J. Psychopharmacol. 14, 214–221.
Berger, J.R., Nath, A., 1997. HIV dementia and the basal ganglia. Intervirology 40,
122–131.
Brew, B.J., 2004. Evidence for a change in AIDS dementia complex in the era of highly
active antiretroviral therapy and the possibility of new forms of AIDS dementia
complex. Aids 18, S75–S78.
Chiriboga, C.A., Fleishman, S., Champion, S., Gaye-Robinson, L., Abrams, E.J., 2005.
Incidence and prevalence of HIV encephalopathy in children with HIV infection re-
ceiving highly active anti-retroviral therapy (HAART). J. Pediatr. 146, 402–407.
Cohen, S., Caan, M.W., Mutsaerts, H.J., Scherpbier, H.J., Kuijpers, T.W., Reiss, P., Majoie,
C.B., Pajkrt, D., 2016. Cerebral injury in perinatally HIV-infected children compared
to matched healthy controls. Neurology 86, 19–27.
Cooper, E.R., Hanson, C., Diaz, C., Mendez, H., Abboud, R., Nugent, R., Pitt, J., Rich, K.,
Rodriguez, E.M., Smeriglio, V., Grp, W.I.T.S., 1998. Encephalopathy and progression
of human immunodeficiency virus disease in a cohort of children with perinatally
acquired human immunodeficiency virus infection. J. Pediatr. 132, 808–812.
Fennema-Notestine, C., Ellis, R.J., Archibald, S.L., Jernigan, T.L., Letendre, S.L.,
Notestine, R.J., Taylor, M.J., Theilmann, R.J., Julaton, M.D., Croteau, D.J., Wolfson,
T., Heaton, R.K., Gamst, A.C., Franklin Jr., D.R., Clifford, D.B., Collier, A.C., Gelman,
B.B., Marra, C., McArthur, J.C., McCutchan, J.A., Morgello, S., Simpson, D.M., Grant,
I., Group, C, 2013. Increases in brain white matter abnormalities and subcortical gray
matter are linked to CD4 recovery in HIV infection. J. Neuro-Oncol. 19, 393–401.
Fischl, B., Salat, D.H., Busa, E., Albert, M., Dieterich, M., Haselgrove, C., van der Kouwe,
A., Killiany, R., Kennedy, D., Klaveness, S., Montillo, A., Makris, N., Rosen, B., Dale,
A.M., 2002. Whole brain segmentation: automated labeling of neuroanatomical
structures in the human brain. Neuron 33, 341–355.
George, R., Andronikou, S., du Plessis, J., du Plessis, A.M., Van Toorn, R., Maydell, A.,
2009. Central nervous system manifestations of HIV infection in children. Pediatr.
Radiol. 39, 575–585.
Giedd, J.N., 2004. Structural magnetic resonance imaging of the adolescent brain.
Adolesc. Brain Dev. 1021, 77–85.
Gutman, B.A., Wang, Y.L., Rajagopalan, P., Toga, A.W., Thompson, P.M., 2012. Shape
Matching with Medial Curves and 1-D Group-Wise Registration. 2012 9th Ieee
International Symposium on Biomedical Imaging (Isbi). pp. 716–719.
Gutman, B.A., Madsen, S.K., Toga, A.W., Thompson, P.M., 2013. A Family of Fast
Spherical Registration Algorithms for Cortical Shapes. Springer International
Publishing, Cham, pp. 246–257.
Gutman, B.A., Jahanshad, N., Ching, C.R.K., Wang, Y.L., Kochunov, P.V., Nichols, T.E.,
Thompson, P.M., 2015. Medial Demons Registration Localizes the Degree of Genetic
Influence over Subcortical Shape Variability: An N=1480 Meta-Analysis. 2015 IEEE
12th International Symposium on Biomedical Imaging (ISBI). pp. 1402–1406.
Heaton, R.K., Grant, I., Butters, N., White, D.A., Kirson, D., Atkinson, J.H., McCutchan,
J.A., Taylor, M.J., Kelly, M.D., Ellis, R.J., et al., 1995. The HNRC 500—neu-
ropsychology of HIV infection at different disease stages. HIV Neurobehavioral
Research Center. J. Int. Neuropsychol. Soc. 1, 231–251.
Herting, M.M., Uban, K.A., Williams, P.L., Gautam, P., Huo, Y., Malee, K., Yogev, R.,
Csernansky, J., Wang, L., Nichols, S., Van Dyke, R., Sowell, E.R., 2015. Default mode
connectivity in youth with perinatally acquired HIV. Medicine (Baltimore) 94, e1417.
Hoare, J., Fouche, J.P., Phillips, N., Joska, J.A., Donald, K.A., Thomas, K., Stein, D.J.,
2015. Clinical associations of white matter damage in cART-treated HIV-positive
children in South Africa. J. Neuro-Oncol. 21, 120–128.
Hoare, J., Fouche, J.P., Phillips, N., Joska, J.A., Myer, L., Zar, H.J., Stein, D.J., 2018.
Structural brain changes in perinatally HIV-infected young adolescents in South
B.S.C. Wade, et al. NeuroImage: Clinical 23 (2019) 101810
7
Africa. Aids 32, 2707–2718.
Jernigan, T.L., Archibald, S.L., Fennema-Notestine, C., Taylor, M.J., Theilmann, R.J.,
Julaton, M.D., Notestine, R.J., Wolfson, T., Letendre, S.L., Ellis, R.J., Heaton, R.K.,
Gamst, A.C., Franklin Jr., D.R., Clifford, D.B., Collier, A.C., Gelman, B.B., Marra, C.,
McArthur, J.C., McCutchan, J.A., Morgello, S., Simpson, D.M., Grant, I., Group, C,
2011. Clinical factors related to brain structure in HIV: the CHARTER study. J. Neuro-
Oncol. 17, 248–257.
Jorgensen, K.N., Nesvag, R., Gunleiksrud, S., Raballo, A., Jonsson, E.G., Agartz, I., 2016.
First- and second-generation antipsychotic drug treatment and subcortical brain
morphology in schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 266, 451–460.
Khan, A.R., Wang, L., Beg, M.F., 2008. FreeSurfer-initiated fully-automated subcortical
brain segmentation in MRI using large deformation diffeomorphic metric mapping.
Neuroimage 41, 735–746.
Lewis-de Los Angeles, C.P., Alpert, K.I., Williams, P.L., Malee, K., Huo, Y., Csernansky,
J.G., Yogev, R., Van Dyke, R.B., Sowell, E.R., Wang, L., Pediatric, H.I.V.A.C.S, 2016.
Deformed subcortical structures are related to past HIV disease severity in youth with
perinatally acquired HIV infection. J. Pediatric. Infect. Dis. Soc. 5, S6–S14.
Li, J., Gao, L., Wen, Z., Zhang, J., Wang, P., Tu, N., Lei, H., Lin, F., Gui, X., Wu, G., 2018.
Structural covariance of Gray matter volume in HIV vertically infected adolescents.
Sci. Rep. 8, 1182.
Patel, K., Ming, X., Williams, P.L., Robertson, K.R., Oleske, J.M., Seage 3rd, G.R.,
International Maternal Pediatric Adolescent, A.C.T.C.S.T, 2009. Impact of HAART
and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perina-
tally infected children and adolescents. Aids 23, 1893–1901.
Paul, R., Apornpong, T., Prasitsuebsai, W., Puthanakit, T., Saphonn, V., Aurpibul, L.,
Kosalaraksa, P., Kanjanavanit, S., Luesomboon, W., Ngampiyaskul, C., Suwanlerk, T.,
Chettra, K., Shearer, W.T., Valcour, V., Ananworanich, J., Kerr, S., 2018. Cognition,
emotional health, and immunological markers in children with long-term non-
progressive HIV. J. Acquir. Immune Defic. Syndr. 77, 417–426.
Paul, R., Prasitsuebsai, W., Jahanshad, N., Puthanakit, T., Thompson, P., Aurpibul, L.,
Hansudewechakul, R., Kosalaraksa, P., Kanjanavanit, S., Ngampiyaskul, C.,
Luesomboon, W., Lerdlum, S., Pothisri, M., Visrutaratna, P., Valcour, V., Nir, T.M.,
Saremi, A., Kerr, S., Ananworanich, J., Pediatric Randomized Early versus Deferred
Initiation in, C, Thailand Study, G, 2018b. Structural neuroimaging and neu-
ropsychologic signatures in children with vertically acquired HIV. Pediatr. Infect. Dis.
J. 37, 662–668.
Puthanakit, T., Saphonn, V., Ananworanich, J., Kosalaraksa, P., Hansudewechakul, R.,
Vibol, U., Kerr, S.J., Kanjanavanit, S., Ngampiyaskul, C., Wongsawat, J.,
Luesomboon, W., Ngo-Giang-Huong, N., Chettra, K., Cheunyam, T., Suwarnlerk, T.,
Ubolyam, S., Shearer, W.T., Paul, R., Mofenson, L.M., Fox, L., Law, M.G., Cooper,
D.A., Phanuphak, P., Vun, M.C., Ruxrungtham, K., Group, P.S., 2012. Early versus
deferred antiretroviral therapy for children older than 1 year infected with HIV
(PREDICT): a multicentre, randomised, open-label trial. Lancet Infect. Dis. 12,
933–941.
Puthanakit, T., Ananworanich, J., Vonthanak, S., Kosalaraksa, P., Hansudewechakul, R.,
van der Lugt, J., Kerr, S.J., Kanjanavanit, S., Ngampiyaskul, C., Wongsawat, J.,
Luesomboon, W., Vibol, U., Pruksakaew, K., Suwarnlerk, T., Apornpong, T.,
Ratanadilok, K., Paul, R., Mofenson, L.M., Fox, L., Valcour, V., Brouwers, P.,
Ruxrungtham, K., Group, P.S., 2013. Cognitive function and neurodevelopmental
outcomes in HIV-infected children older than 1 year of age randomized to early
versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study.
Pediatr. Infect. Dis. J. 32, 501–508.
Randall, S.R., Warton, C.M.R., Holmes, M.J., Cotton, M.F., Laughton, B., van der Kouwe,
A.J.W., Meintjes, E.M., 2017. Larger subcortical gray matter structures and smaller
corpora callosa at age 5 years in HIV infected children on early ART. Front.
Neuroanat. 11, 95.
Raskino, C., Pearson, D.A., Baker, C.J., Lifschitz, M.H., O'Donnell, K., Mintz, M., Nozyce,
M., Brouwers, P., McKinney, R.E., Jimenez, E., Englund, J.A., 1999. Neurologic,
neurocognitive, and brain growth outcomes in human immunodeficiency virus-in-
fected children receiving different nucleoside antiretroviral regimens. Pediatric AIDS
Clinical Trials Group 152 Study Team. Pediatrics 104, e32.
Sacktor, N., McDermott, M.P., Marder, K., Schifitto, G., Selnes, O.A., McArthur, J.C.,
Stern, Y., Albert, S., Palumbo, D., Kieburtz, K., De Marcaida, J.A., Cohen, B., Epstein,
L., 2002. HIV-associated cognitive impairment before and after the advent of com-
bination therapy. J. Neuro-Oncol. 8, 136–142.
Safriel, Y.I., Haller, J.O., Lefton, D.R., Obedian, R., 2000. Imaging of the brain in the HIV-
positive child. Pediatr. Radiol. 30, 725–732.
Sarma, M.K., Nagarajan, R., Keller, M.A., Kumar, R., Nielsen-Saines, K., Michalik, D.E.,
Deville, J., Church, J.A., Thomas, M.A., 2014. Regional brain gray and white matter
changes in perinatally HIV-infected adolescents. Neuroimage Clin. 4, 29–34.
Shanbhag, M.C., Rutstein, R.M., Zaoutis, T., Zhao, H., Chao, D., Radcliffe, J., 2005.
Neurocognitive functioning in pediatric human immunodeficiency virus infection:
effects of combined therapy. Arch. Pediatr. Adolesc. Med. 159, 651–656.
Tate, D.F., Wade, B.S., Velez, C.S., Drennon, A.M., Bolzenius, J., Gutman, B.A.,
Thompson, P.M., Lewis, J.D., Wilde, E.A., Bigler, E.D., Shenton, M.E., Ritter, J.L.,
York, G.E., 2016. Volumetric and shape analyses of subcortical structures in United
States service members with mild traumatic brain injury. J. Neurol. 263, 2065–2079.
Tate, D.F., Wade, B.S.C., Velez, C.S., Drennon, A.M., Bolzenius, J.D., Cooper, D.B.,
Kennedy, J.E., Reid, M.W., Bowles, A.O., Thompson, P.M., Gutman, B.A., Lewis, J.D.,
Ritter, J.L., York, G.E., Bigler, E.D., 2018. Subcortical shape and neuropsychological
function among U.S. service members with mild traumatic brain injury. Brain Imag.
Behav.
Turner, A.H., Greenspan, K.S., van Erp, T.G.M., 2016. Pallidum and lateral ventricle
volume enlargement in autism spectrum disorder. Psychiatry Res. Neuroimaging 252,
40–45.
Uban, K.A., Herting, M.M., Williams, P.L., Ajmera, T., Gautam, P., Huo, Y., Malee, K.M.,
Yogev, R., Csernansky, J.G., Wang, L., Nichols, S.L., Sowell, E.R., Pediatric, H.C., the
Pediatric Imaging, N., Genetics, S, 2015. White matter microstructure among youth
with perinatally acquired HIV is associated with disease severity. Aids 29,
1035–1044.
van Erp, T.G., Hibar, D.P., Rasmussen, J.M., Glahn, D.C., Pearlson, G.D., Andreassen,
O.A., Agartz, I., Westlye, L.T., Haukvik, U.K., Dale, A.M., Melle, I., Hartberg, C.B.,
Gruber, O., Kraemer, B., Zilles, D., Donohoe, G., Kelly, S., McDonald, C., Morris,
D.W., Cannon, D.M., Corvin, A., Machielsen, M.W., Koenders, L., de Haan, L.,
Veltman, D.J., Satterthwaite, T.D., Wolf, D.H., Gur, R.C., Gur, R.E., Potkin, S.G.,
Mathalon, D.H., Mueller, B.A., Preda, A., Macciardi, F., Ehrlich, S., Walton, E., Hass,
J., Calhoun, V.D., Bockholt, H.J., Sponheim, S.R., Shoemaker, J.M., van Haren, N.E.,
Hulshoff Pol, H.E., Ophoff, R.A., Kahn, R.S., Roiz-Santianez, R., Crespo-Facorro, B.,
Wang, L., Alpert, K.I., Jonsson, E.G., Dimitrova, R., Bois, C., Whalley, H.C., McIntosh,
A.M., Lawrie, S.M., Hashimoto, R., Thompson, P.M., Turner, J.A., 2016. Subcortical
brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy
controls via the ENIGMA consortium. Mol. Psychiatry 21, 547–553.
Van Rie, A., Mupuala, A., Dow, A., 2008. Impact of the HIV/AIDS epidemic on the
neurodevelopment of preschool-aged children in Kinshasa, Democratic Republic of
the Congo. Pediatrics 122, E123–E128.
Wade, B.S., Valcour, V.G., Wendelken-Riegelhaupt, L., Esmaeili-Firidouni, P., Joshi, S.H.,
Gutman, B.A., Thompson, P.M., 2015. Mapping abnormal subcortical brain mor-
phometry in an elderly HIV+ cohort. Neuroimage Clin. 9, 564–573.
Wade, B.S., Joshi, S.H., Njau, S., Leaver, A.M., Vasavada, M., Woods, R.P., Gutman, B.A.,
Thompson, P.M., Espinoza, R., Narr, K.L., 2016. Effect of electroconvulsive therapy
on striatal morphometry in major depressive disorder. Neuropsychopharmacology
41, 2481–2491.
Wade, B.S.C., Sui, J., Njau, S., Leaver, A.M., Vasvada, M., Gutman, B.A., Thompson, P.M.,
Espinoza, R., Woods, R.P., Abbott, C.C., Narr, K.L., Joshi, S.H., 2017. Data-driven
cluster selection for subcortical shape and cortical thickness predicts recovery from
depressive symptoms. In: 2017 IEEE 14th International Symposium on Biomedical
Imaging (ISBI 2017), pp. 502–506.
Wright, P.W., Pyakurel, A., Vaida, F.F., Price, R.W., Lee, E., Peterson, J., Fuchs, D.,
Zetterberg, H., Robertson, K.R., Walter, R., Meyerhoff, D.J., Spudich, S.S., Ances,
B.M., 2016. Putamen volume and its clinical and neurological correlates in primary
HIV infection. Aids 30, 1789–1794.
B.S.C. Wade, et al. NeuroImage: Clinical 23 (2019) 101810
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... [12,15] Commonly, within the PHIV population the alterations found in brain structure have been usually related to a poor immunovirological status and to the lack of an effective antiretroviral treatment. [9,14,17,18] Taking into account all these factors and the previous results, the present study attempts to determine the characteristic pattern of cortical thinning and subcortical (total and regional) in a predominant viral suppressed perinatal HIV population with an average cognitive functioning and compare it with an HIVcontrol group strictly matched by age, sex, level of education, and socioeconomic status. Mindful of the need to restrict the number of statistical comparisons, we also studied the effect of HIV status on all main subregions of the basal ganglia (BG) volumes. ...
... Secondly, we tested the hypothesis that a worse immunovirological status will be associated with smaller volumes of the BG since it has been reported to be particularly impacted. [11,12,14,[16][17][18] 2. Materials and methods ...
... The association between a low CD4 T-cell count and reduced subcortical regional volumes may indicate that prolonged immunosuppression could play and additional role in CNS damage, explaining the better brain development of well controlled patients. In line with this, Wade et al [18] described increased rates of volume growth in determined subcortical areas in children with higher CD4 counts and similarly, Cohen et al [3] published that longer time with low CD4 T-cell counts was associated with a lower total GM volume. ...
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Brain atrophy has been observed in perinatally HIV-infected patients (PHIV) despite initiation on combined antiretroviral treatment (cART), but neuroimaging studies are limited. We aimed to evaluate cortical thickness (CT) and subcortical gray matter (GM) volumes of PHIV youths with stable immunovirological situation and with a normal daily performance.A prospective cross-sectional study was conducted. A total of 25 PHIV patients on cART and 25 HIV-negative (HIV-) controls matched by age, sex, level of education, and socioeconomic status underwent a magnetic resonance imaging scan. CAT12 toolbox was used to extract CT values from T1w images using parcellations from Desikan-Killiany atlas (DK40). To measure regional brain volumes, native segmented images were parceled in regions of interest according to the Neuromorphometrics Atlas. Neuropsychological assessment and psychopathological symptoms were documented.Fifty participants were included (60% females, median age 20 years [interquartile range, IQR 19-23], 64% Whites). No differences regarding neuropsychological tests or psychopathological symptoms were found between groups (all P > .05). All participants presented an average performance in the Fluid Intelligence (FI) test (PHIV mean: -0.12, HIV- mean: 0.24), When comparing CT, PHIV-infected patients showed thinner cortices compared with their peers in fusiform gyrus (P = .000, P = .009), lateral-orbitofrontal gyrus (P = .006, P = .0024), and right parsobitalis gyrus (P = .047). Regarding subcortical GM volumes, PHIV patients showed lower right amygdala (P = .014) and left putamen (P = .016) volumes when compared with HIV- controls. Within the PHIV group, higher CD4 count was associated with higher volumes in right putamen (B = 0.00000038, P = .045). Moreover, increased age at cART initiation and lower nadir CD4 count was associated with larger volumes in left accumbens (B = 0.0000046, P = .033; B = -0.00000008, P = .045, respectively).PHIV patients showed thinner cortices of areas in temporal, orbito-frontal and occipital lobes and lower volumes of subcortical GM volumes when compared with the HIV- control group, suggesting cortical and subcortical brain alterations in otherwise neuroasymptomatic patients. Nevertheless, larger and longitudinal studies are required to determine the impact of HIV on brain structure in PHIV patients and to further identify risk and protective factors that could be implicated.
... These findings in the CHER children are consistent with other studies demonstrating HIV-related irregularities in brain structure and WM integrity across childhood (Blokhuis et al., 2017(Blokhuis et al., , 2019Hoare et al., 2019;Lewis-de los Angeles et al., 2016Wade et al., 2019;Yadav et al., 2017;Yu et al., 2019). Although a single MRI modality can identify pathological brain alterations, in isolation none can provide a comprehensive picture of the impact of HIV on brain structure and function. ...
... Our results suggest that HIV may affect globus pallidus more than other components of the basal ganglia. In a cohort of Thai CPHIV, there was shape deformation of the right pallidal surface and baseline CD4 count was negatively associated with left globus pallidus volume (Wade et al., 2019). Shape deformation has also been negatively associated with peak viral load in adolescents (Lewis-de los Angeles et al., 2016). ...
... These findings in the CHER children are consistent with other studies demonstrating HIV-related irregularities in brain structure and WM integrity across childhood (Blokhuis et al., 2017(Blokhuis et al., , 2019Hoare et al., 2019;Lewis-de los Angeles et al., 2016Wade et al., 2019;Yadav et al., 2017;Yu et al., 2019). Although a single MRI modality can identify pathological brain alterations, in isolation none can provide a comprehensive picture of the impact of HIV on brain structure and function. ...
... Our results suggest that HIV may affect globus pallidus more than other components of the basal ganglia. In a cohort of Thai CPHIV, there was shape deformation of the right pallidal surface and baseline CD4 count was negatively associated with left globus pallidus volume (Wade et al., 2019). Shape deformation has also been negatively associated with peak viral load in adolescents (Lewis-de los Angeles et al., 2016). ...
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Children with perinatally acquired HIV (CPHIV) have poor cognitive outcomes despite early combination antiretroviral therapy (cART). While CPHIV-related brain alterations can be investigated separately using proton magnetic resonance spectroscopy (1 H-MRS), structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), and functional MRI (fMRI), a set of multimodal MRI measures characteristic of children on cART has not been previously identified. We used the embedded feature selection of a logistic elastic-net (EN) regularization to select neuroimaging measures that distinguish CPHIV from controls and measured their classification performance via the area under the receiver operating characteristic curve (AUC) using repeated cross validation. We also wished to establish whether combining MRI modalities improved the models. In single modality analysis, sMRI volumes performed best followed by DTI, whereas individual EN models on spectroscopic, gyrification, and cortical thickness measures showed no class discrimination capability. Adding DTI and 1 H-MRS in basal measures to sMRI volumes produced the highest classification performance validation accuracy = 85 % AUC = 0.80 $$ \left(\mathrm{validation}\ \mathrm{accuracy}=85\%,\mathrm{AUC}=0.80\right) $$ . The best multimodal MRI set consisted of 22 DTI and sMRI volume features, which included reduced volumes of the bilateral globus pallidus and amygdala, as well as increased mean diffusivity (MD) and radial diffusivity (RD) in the right corticospinal tract in cART-treated CPHIV. Consistent with previous studies of CPHIV, select subcortical volumes obtained from sMRI provide reasonable discrimination between CPHIV and controls. This may give insight into neuroimaging measures that are relevant in understanding the effects of HIV on the brain, thereby providing a starting point for evaluating their link with cognitive performance in CPHIV.
... Additionally, shape analysis can localise regional atrophy of subcortical structures which may be insensitive to volumetric methods [14]. However, shape analysis in PWH is limited to samples with low proportions of antiretroviral treatment [15], poor viral control [16], or younger age [17]. Although a crosssectional shape study has suggested an accelerated aging effect in younger PWH [18], there is a need for longitudinal shape studies in older age groups. ...
... This is distinct from previous cross-sectional shape studies where cART was taken by the majority, but not all, participants [15,16], or not reported [18], and with 20-30% of the PWH having detectable viral loads [15,16,18]. To the best of our knowledge, the only previous longitudinal study of shape analysis in PWH was in a paediatric cohort which found no longitudinal shape differences by HIV status [17]. The presence of an overall volumetric effect rather than a shape effect indicates that the entire structure is affected rather than regional areas [33]. ...
Article
Objective: We aimed to examine the relative contributions of HIV infection, age, and cardiovascular risk factors to subcortical brain atrophy in people with HIV (PWH). Design: Longitudinal observational study. Methods: Virally suppressed PWH with low neuropsychological confounds (n = 75) and demographically matched HIV-negative controls (n = 31) completed baseline and 18-month follow-up MRI scans, neuropsychological evaluation, cardiovascular assessments, and HIV laboratory tests. PWH were evaluated for HIV associated neurocognitive disorder (HAND). Subcortical volumes were extracted with Freesurfer after removal of white matter hyperintensities. Volumetric and shape analyses were conducted using linear mixed-effect models incorporating interactions between age, time, and each of HIV status, HAND status, HIV disease factors, and cardiovascular markers. Results: Across baseline and follow-up PWH had smaller volumes of most subcortical structures compared to HIV-negative participants. Additionally, over time older PWH had a more rapid decline in caudate volumes (p = 0.041), predominantly in the more severe HAND subgroups (p = 0.042). Higher CD4 counts had a protective effect over time on subcortical structures for older participants with HIV. Increased cardiovascular risk factors were associated with smaller volumes across baseline and follow-up for most structures, although a more rapid decline over time was observed for striatal volumes. There were no significant shape analyses findings. Conclusions: The study demonstrates a three-hit model of general (as opposed to localised) subcortical injury in PWH: HIV infection associated with smaller volumes of most subcortical structures, HIV infection and aging synergy in the striatum, and cardiovascular-related injury linked to early and more rapid striatal atrophy.
... Up to now, only two other longitudinal studies have investigated brain development in PHIV-positive children transitioning into adulthood [15,16]. Both studies were limited by a follow-up time of only one year, as well as by the fact that they investigated brain development from a limited perspective, primarily focusing on either subcortical structures using 1.5T MRI [15] or solely performing region of interest analysis, studying grey matter and cortical thickness development [16]. ...
... Up to now, only two other longitudinal studies have investigated brain development in PHIV-positive children transitioning into adulthood [15,16]. Both studies were limited by a follow-up time of only one year, as well as by the fact that they investigated brain development from a limited perspective, primarily focusing on either subcortical structures using 1.5T MRI [15] or solely performing region of interest analysis, studying grey matter and cortical thickness development [16]. Nonetheless, in line with the results of our findings, the effect of HIV on brain morphology was suggested to be subtle. ...
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Objective: Cross-sectional studies, including one from our NOVICE cohort (Neurological Visual and Cognitive performance in children with treated perinatally acquired HIV [PHIV] compared to matched HIV-negative controls), have revealed that the brains of children with PHIV have lower white matter (WM) and grey matter (GM) volumes, more WM hyperintensities (WMH), and poorer WM integrity. This longitudinal study investigates whether these differences change over time. Methods: We approached all NOVICE participants to repeat MRI after 4.6 ± 0.3 years, measuring total WM and GM volume, WMH volume and WM integrity, obtained by T1-weighted-, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor imaging (DTI), respectively. We compared rates of change between groups using multivariable linear mixed effects models, adjusted for sex and age at enrollment. We investigated determinants of developmental deviation, and explored associations with cognitive development. Results: 20/31(65%) PHIV-positive, and 20/37(54%) HIV-negative participants underwent follow-up MRI. Groups did not significantly differ in terms of age and sex. Over time, we found no statistically different changes between groups for WM and WMH volumes, and for WM integrity (p-values>0.1). Total GM volume decreased significantly less in PHIV (group*time 10 mL, 95%CI -1 to 20, p-value=0.078); but this difference in rate of change lost statistical significance after additional adjustment for height (group*time 9 mL, 95%CI -2 to 20, p-value=0.112). We found no HIV-associated determinants for potential reduced GM pruning, nor associations with cognitive development. Conclusions: while using long-term antiretroviral treatment, structural brain development of adolescents growing up with perinatally acquired HIV appears largely normal.
... Although both groups showed developmental cortical thinning and reductions in gray matter volume after one year, their topography differed, leading the authors to suggest delayed cortical maturation with PHIV. In contrast and in a younger cohort, the PREDICT study performed shape analysis of subcortical structures over two time points one year apart in an early adolescent cohort of Thai youth (mean age 11 at baseline) with PHIV, PHEU, or uninfected and unexposed [74]. Although there were group differences in the pallidum at baseline, these attenuated over one year and group effects were considered minor by the authors; however, within the group with PHIV intriguing associations of CD4 count with pallidum shape and volume were observed. ...
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Purpose of Review Perinatally acquired HIV infection (PHIV) can confer neurodevelopmental risk. As children with PHIV increasingly survive through adolescence and into adulthood, understanding its long-term central nervous system (CNS) impacts is critical for maximizing adult outcomes and quality of life. Recent Findings Recently published neurocognitive and neuroimaging findings show impacts on the CNS associated with early HIV disease progression that endure into adolescence and young adulthood. Although developmental trajectories in adolescence largely appear stable, further research on maturational processes is indicated. Summary Although early antiretroviral therapy in infancy appears to be protective, it is not universally available and current youth largely developed without its benefit. The neurocognitive effects of HIV and the multiple other risks to neurodevelopment experienced by youth with PHIV call for further longitudinal research and a multifaceted approach to prevention and intervention.
... In other studies, no differences have been seen in children's cognition in relation to age of antiretroviral treatment (ART) initiation [4]. The second factor described in many studies, is the positive influence of the immunovirological control on CNS [39]. ...
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Introduction and aim: Perinatal transmission of human immunodeficiency virus (PHIV) is considered a chronic disease that has highlighted several cognitive deficits. From birth to early adulthood, cognition is known to play a fundamental role. However, although neurocognitive processes associated with PHIV have been extensively described by psychometric testing, data is scarce on neural activity from functional magnetic resonance imaging (fMRI) which provides in vivo physiological information. Subjects and methods: We studied described impaired cognitive processes using fMRI on a group of PHIV adolescents with good immunovirological indications and healthy matched controls. Psychological status and neurocognitive functions were also assessed. Results: There were no significant differences between HIV+ and HIV- groups, either on neurocognitive testing nor in fMRI activity for phonological fluency tasks. Prolonged duration of cART was positively associated with greater brain activity in left inferior frontal gyrus (LIFG) which could indicate functional compensation. Conclusions: These results suggest that neural activity through fMRI in PHIV adolescents with good daily functioning and good immunovirological control may be similar to their peers.
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Objective: To describe the structural brain changes, neurocognitive and mental health associations in adolescents perinatally infected with HIV-1 infection. Design: Cross-sectional. Methods: 204 adolescents with perinatally acquired HIV and 44 uninfected frequency matched controls aged 9 to 11 years were enrolled within the Cape Town Adolescent Antiretroviral Cohort. Diffusion tensor imaging and structural brain magnetic resonance imaging (MRI) was done to determine fractional anisotropy (FA), mean diffusivity (MD), gray and white matter volumes, cortical thickness and cortical surface area. Correlation coefficients were calculated between total gray and white matter volume, cortical surface area, cortical thickness, whole brain FA and whole brain MD and clinical and laboratory parameters including general intellectual functioning, Becks Youth Inventory, Child Motivation Scale and Child Behavior Checklist. Results: HIV infected adolescents performed worse than controls on the Wechsler Abbreviated Scale of Intelligence (WASI)(p = <0.01). HIV infected adolescents had significant FA decreases, MD increases, and decreases in cerebral gray matter volumes, cortical surface area and decreased gyrification. Whole brain mean FA was significantly reduced in the HIV infected group (p = 0. 031). There were significant correlation coefficients between greater total gray (p = 0.008) and white matter volume (p = 0.004) with the WASI and the Becks self-concept subscale (p = 0.038). Lower whole brain FA was associated with higher scores on the Becks anger (p = 0.018) and disruptive behavior subscales (p = 0.031). Higher whole brain MD was associated with apathy (p = 0.046). Conclusion: The pattern of increased risk of white matter microstructure alterations, smaller gray matter volumes, reduced cortical surface area and decreased gyrification, suggests abnormal neurodevelopment in perinatally infected younger adolescents.
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Background: HIV-infected children with long-term nonprogressive disease (LTNPs) eventually convert to a progressive disease type, yet the extent to which these children experience the cognitive and emotional symptoms observed in typical progressive HIV (Progressors) is unknown. Methods: Eighty-eight LTNPs, 53 Progressors, and 323 healthy controls completed annual assessments of cognitive and emotional health as part of a prospective study. The two HIV-infected groups and the healthy controls were matched on age and sex distribution at enrollment. Plasma HIV RNA, T-cell counts/percentages, activated monocytes, perivascular monocytes, and markers of macrophage activation (sCD163 and sCD14) were compared by progression subtype. Cognitive and emotional outcomes were compared using cross-sectional linear regression analysis and longitudinal sensitivity models. Results: LTNPs exhibited the same cognitive phenotype and emotional dysregulation as Progressors, with worse outcomes in both groups compared to controls. Additionally, cognitive and emotional symptoms were evident before children reached the minimum age for LTNP designation (8 years). Baseline plasma HIV RNA, sCD163, activated monocytes, and perivascular monocytes were lower in LTNPs versus Progressors, with no difference in T-cell counts/percentages or sCD14 levels. Most LTNPs converted to a progressive disease subtype during the study, with similar cognitive and emotion profiles between these subgroups. Conclusions: Pediatric LTNPs experience cognitive and emotional difficulties that mirror symptoms of progressive disease. The abnormalities are present at young ages and persist independent of plasma T-cell counts. The findings highlight the neurodevelopmental risk of pediatric HIV, even in those with early innate disease control.
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Background: Children with vertically acquired human immunodeficiency virus (HIV) exhibit persistent cognitive impairments, yet the corresponding neuroimaging signature of vertical infection remains unclear. Methods: Fifty healthy control children and 51 vertically infected children were included in the study. The HIV-infected group consisted of survivors who had not received antiretroviral therapy (ART) at birth. The HIV-infected group averaged 11.4 (2.5) years of age, with a median CD4 count of 683 cells/mm. Most (71%) of the HIV-infected children were on ART for a median of 34 months (range: 33-42) with HIV RNA <40 copies/ml in 89% of the sample. The HIV-uninfected group averaged 10.6 (2.6) years of age. Magnetic resonance imaging was acquired to determine volumes of the caudate, putamen, thalamus, pallidum, hippocampus, nucleus accumbens, total white matter, total gray matter, and cortical gray matter. Correlational analyses examined the degree of shared variance between brain volumes and both cognitive performances and laboratory markers of disease activity (T-cells and plasma viral load). Results: HIV-infected children exhibited larger volumes of the caudate, nucleus accumbens, total gray matter, and cortical gray matter when compared to the controls. Volumetric differences were predominately evident in children under 12 years of age. HIV-infected children performed worse than controls on most neuropsychological tests, though neither cognitive performances nor laboratory markers corresponded to brain volumes in the HIV-infected children. Conclusions: Outcomes of the present study suggest abnormal brain maturation among HIV-infected pediatric survivors. Longitudinal studies of brain integrity and related resilience factors are needed to determine the impact of neuroimaging abnormalities on psychosocial function in pediatric HIV.
Conference Paper
Patients with major depressive disorder (MDD) who do not achieve full symptomatic recovery after antidepressant treatment have a higher risk of relapse. Compared to pharmacotherapies, electroconvulsive therapy (ECT) more rapidly produces a greater extent of response in severely depressed patients. However, prediction of which candidates are most likely to improve after ECT remains challenging. Using structural MRI data from 42 ECT patients scanned prior to ECT treatment, we developed a random forest classifier based on data-driven shape cluster selection and cortical thickness features to predict remission. Right hemisphere hippocampal shape and right inferior temporal cortical thickness was most predictive of remission, with the predicted probability of recovery decreasing when these regions were thicker prior to treatment. Remission was predicted with an average 73% balanced accuracy. Classification of MRI data may help identify treatment-responsive patients and aid in clinical decision-making. Our results show promise for the development of personalized treatment strategies.