Impairments in memory and hippocampal function in HIV-positive vs HIV-negative women: a preliminary study.
ABSTRACT Neurocognitive studies of HIV typically target executive functions dependent on frontostriatal circuitry. The integrity of medial temporal systems has received considerably less attention despite high hippocampal viral load. Studies also predominately involve HIV+ men, though HIV+ women may be at increased risk for cognitive dysfunction due to the high prevalence of psychosocial/mental health problems and lower educational attainment. Our aim was to conduct a preliminary investigation of episodic memory and its neural correlates in HIV-infected and at-risk uninfected women.
Participants included 54 HIV+ and 12 HIV- women (mean age = 43 years; 86% African American) recruited from the Chicago site of the Women's Interagency HIV Study. Participants completed standardized tests of verbal and visual episodic memory, working memory, and executive function. A subset of 11 women also underwent functional MRI during a delayed verbal episodic memory task.
HIV serostatus predicted significantly lower immediate and delayed verbal episodic memory, working memory, and visual memory. Preliminary neuroimaging findings revealed group differences in bilateral hippocampal function, with HIV+ women showing decreased activation during encoding and increased activation during delayed recognition. These alterations correlated with worse episodic verbal memory.
Verbal episodic memory deficits are evident in HIV+ women and may be associated with hippocampal dysfunction at both encoding and retrieval.
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ABSTRACT: HIV-1 associated neurocognitive deficits are increasing in prevalence, although the neuronal basis for these deficits is unclear. HIV-1 Tg rats constitutively express 7 of 9 HIV-associated proteins, and may be useful for studying the neuropathological substrates of HIV-1 associated neurocognitive disorders (HAND). In this study, adult female HIV-1 Tg rats and F344 control rats had similar growth rates, estrous cyclicity and startle reflex inhibition to a visual prepulse stimulus. Medium spiny neurons (MSNs) in the nucleus accumbens (NAcc) were ballistically-labeled utilizing the indocarbocyanine dye DiI. The branching complexity of MSNs in the NAcc was significantly decreased in HIV-1 Tg rats, relative to controls; moreover, the shorter length and decreased volume of dendritic spines, but unchanged head diameter, in HIV-1 Tg rats suggested a reduction of longer spines and an increase in shorter, less projected spines, indicating a population shift to a more immature spine phenotype. Collectively, these results from HIV-1 Tg female rats indicated significant synaptodendritic alterations of MSNs in the NAcc occur as a consequence of chronic, low-level, exposure to HIV-1 associated proteins.Journal of Neuroimmune Pharmacology 07/2014; · 3.17 Impact Factor
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ABSTRACT: The debate regarding neurocognitive functions in the early stages of HIV infection is still ongoing; different studies have reached contrasting conclusions, probably because many of them take into account different cohorts of patients. A main distinction is between HIV seropositive patients infected perinatally, and those infected postnatally. The aim of this paper is to review results on neurocognitive dysfunctions and other types of neurological involvement in a specific cohort of HIV+ patients infected postnatally: hemophilia patients. Such a review is relevant, as HIV seropositive patients infected postnatally are understudied with respect to patients infected perinatally, and as the results of the few studies aiming at comparing them are contrasting. Taken together, the 11 studies reviewed suggest the presence of both long-term neurocognitive dysfunctions and neurological alterations, such as the presence of atrophic changes and lesions in the white matter. The current review may offer new research insights into the neurocognitive dysfunctions in HIV-patients, and on the nature of such dysfunctions.Frontiers in Human Neuroscience 06/2014; · 2.90 Impact Factor
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ABSTRACT: Background Risky decision-making is commonly observed in persons at risk for and infected with HIV and is associated with executive dysfunction. Yet it is currently unknown whether HIV alters brain processing of risk-taking decision-making. Methods This study examined the neural substrate of a risky decision-making task in 21 HIV seropositive (HIV+) and 19 seronegative (HIV-) comparison participants. Functional magnetic resonance imaging was conducted while participants performed the risky- gains task, which involves choosing among safe (20 cents) and risky (40/80 cent win or loss) choices. Linear mixed effects analyses examining group and decision type were conducted. Robust regressions were performed to examine the relationship between nadir CD4 count and Kalichman sexual compulsivity and brain activation in the HIV+ group. The overlap between the task effects and robust regressions was explored. Results Although there were no serostatus effects in behavioral performance on the risky-gains task, HIV+ individuals exhibited greater activation for risky choices in the basal ganglia, i.e. the caudate nucleus, but also in the anterior cingulate, dorsolateral prefrontal cortex, and insula relative to the HIV- group. The HIV+ group also demonstrated reduced functional responses to safe choices in the anterior cingulate and dorsolateral prefrontal cortex relative to the HIV- group. HIV+ individuals with higher nadir CD4 count and greater sexual compulsivity displayed lower differential responses to safe versus risky choices in many of these regions. Conclusions This study demonstrated fronto-striatal loop dysfunction associated with HIV infection during risky decision-making. Combined with similar between-group task behavior, this suggests an adaptive functional response in regions critical to reward and behavioral control in the HIV+ group. HIV-infected individuals with higher CD4 nadirs demonstrated activation patterns more similar to seronegative individuals. This suggests that the severity of past immunosuppression (CD4 nadir) may exert a legacy effect on processing of risky choices in the HIV-infected brain.PLoS ONE 11/2014; · 3.53 Impact Factor
Impairments in memory and
hippocampal function in HIV-positive vs
A preliminary study
P.M. Maki, PhD
M.H. Cohen, MD
K. Weber, RN, BSN
D.M. Little, PhD
D. Fornelli, BS
L.H. Rubin, MA
P. Perschler, MA
F. Gould, PhD
E. Martin, PhD
Objective: Neurocognitive studies of HIV typically target executive functions dependent on fron-
tion despite high hippocampal viral load. Studies also predominately involve HIV? men, though
HIV? women may be at increased risk for cognitive dysfunction due to the high prevalence of
psychosocial/mental health problems and lower educational attainment. Our aim was to conduct a
preliminary investigation of episodic memory and its neural correlates in HIV-infected and at-risk
Methods: Participants included 54 HIV? and 12 HIV? women (mean age ? 43 years; 86% Afri-
can American) recruited from the Chicago site of the Women’s Interagency HIV Study. Partici-
pants completed standardized tests of verbal and visual episodic memory, working memory, and
executive function. A subset of 11 women also underwent functional MRI during a delayed verbal
episodic memory task.
Results: HIV serostatus predicted significantly lower immediate and delayed verbal episodic mem-
ory, working memory, and visual memory. Preliminary neuroimaging findings revealed group dif-
ferences in bilateral hippocampal function, with HIV? women showing decreased activation
during encoding and increased activation during delayed recognition. These alterations corre-
lated with worse episodic verbal memory.
Conclusions: Verbal episodic memory deficits are evident in HIV? women and may be associated
with hippocampal dysfunction at both encoding and retrieval. Neurology®2009;72:1661–1668
ARV ? antiretroviral therapy; CES-D ? Center for Epidemiologic Studies–Depression Scale; fMRI ? functional MRI; HAART ?
highly active antiretroviral therapy; HCV ? hepatitis C virus antibody; HVLT ? Hopkins Verbal Learning Task; ROI ? region of
interest; TE ? echo time; TR ? repetition time; WIHS ? Women’s Interagency HIV Study; WRAT-R ? Wide Range Achievement
Until recently, the functional integrity of medial temporal systems in neuroAIDS has received
little attention despite considerable evidence of hippocampal injury associated with HIV. Brain
viral loads of HIV are particularly high in the hippocampus.1,2Postmortem evidence of neu-
roinflammation by microglial/macrophage activation was found to be high in the hippocampus
of HIV? individuals treated with highly active antiretroviral therapy (HAART), higher even
than levels found in pre-HAART neuropathologic studies.3Regional neurodegeneration of
hippocampus and putamen each contributed unique variance in prediction of antemortem
neurocognitive status in HIV.4A functional MRI (fMRI) study of well-educated HIV? men
demonstrated reduced signal intensity in right posterior hippocampus, right inferior frontal
gyrus, and left lingual gyrus during encoding of scenes.5Further detailed multimodal investiga-
Address correspondence and
reprint requests to Dr. Pauline M.
Maki, University of Illinois at
Chicago, Department of
Psychiatry (MC 913), 912 S
Wood St, Chicago, IL 60612
From the Departments of Psychiatry (P.M.M., D.M.L., D.F., P.P., F.G., E.M.), Psychology (P.M.M., L.H.R.), and Neurology (D.M.L., E.M.),
University of Illinois at Chicago; and Departments of Medicine, Stroger Hospital and Rush University (M.H.C.) and The Core Center (K.W.),
Bureau of Health Services of Cook County, Chicago, IL.
Support information is provided at the end of the article.
Disclosure: The authors report no disclosures.
Disclaimer: The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH,
the University of Illinois at Chicago, Stroger Hospital, or the Cook County Bureau of Health Services.
Copyright © 2009 by AAN Enterprises, Inc.
tion of the functional integrity of medial tem-
poral systems among persons with HIV/AIDS
has considerable potential utility for develop-
ment of targeted treatment.
In the current study, we investigated 1) in-
tegrity of episodic memory in HIV-infected
and at-risk HIV-uninfected women using
standardized neuropsychological tasks; 2) pat-
terns of regional cerebral blood flow in the
hippocampus and parahippocampal gyrus us-
ing fMRI during performance of an episodic
verbal memory test; and 3) relationship be-
tween hippocampal activation patterns and
verbal memory scores. Participants were a
subset of women enrolled in the Chicago site
of the Women’s Interagency HIV Study
(WIHS), a cohort that is quite representative
of women living with HIV/AIDS in the
United States.6,7Neurocognitive complica-
tions of HIV are rarely studied in women,
though women may be at risk for episodic
memory impairment due to poverty, low lit-
eracy levels, substance abuse, poor mental
health, and other risk factors prevalent in our
cohort of predominantly minority urban-
METHODS Subjects. Sixty-three women (51 HIV? and 12
HIV?) were enrolled from the CORE Center/Stroger Hospital
and UIC sites of the Chicago WIHS, a longitudinal multicenter
study of HIV disease progression in women.6,7Participants were
recruited for the cognitive substudy during semiannual WIHS
core visits in 2005–2006. Because of the known effects of ovar-
ian hormone on memory performance, neuropsychological test
sessions were conducted on days 2–4 of the menstrual cycle
based on self-reported menses and any day for women who self-
reported menopause, defined as no menstrual bleeding for the
past 12 consecutive months. All cognitive testing was conducted
at UIC, on average 42 days from the core WIHS visit. Partici-
pants had no evidence of overt cognitive deficits on interview
and no history of HIV-associated dementia or other central neu-
rologic impairment by medical record review or physician re-
port. Women with a history of closed head injury with loss of
consciousness greater than one-half hour, open head injury,
schizophrenia, epilepsy, evidence of intoxication or withdrawal
at testing, or current neuroleptic use were excluded. Additional
exclusion criteria for MRI studies included prohibitive metal im-
plants, claustrophobia, and weight over 250 pounds. The insti-
tutional review boards at UIC and Stroger Hospital approved
the protocol and consent forms, and investigators obtained in-
formed written consent from all subjects. Participants received
monetary incentives as compensation for their time and trans-
Clinical neuropsychological measures. All 63 participants
completed neuropsychological measures of verbal and visual epi-
sodic memory, executive function, and working memory as part
of an extensive test battery requiring approximately 90 minutes
to complete. Test selection was guided by known sensitivity to
HIV-associated cognitive impairment; appropriate difficulty lev-
el; brevity of administration; and comparability with protocols
employed in other neuroAIDS studies (e.g., MACS and CHAR-
TER). The Hopkins Verbal Learning Task (HVLT),8a 12-item
list learning task, was used to measure verbal episodic memory,
indexed by total words recalled after three trials, and delayed free
recall and recognition trials. The Rey Osterrieth Complex Figure
Task served as a measure of visuoconstruction abilities and visual
episodic memory.9Outcome measures included total score on
the copy and 20-minute delayed recall trials. The Stroop Color
Word Test indexed mental speed, attention, and inhibition (ex-
ecutive function)10by computing times to 1) name colors, 2)
read color words, and 3) name the ink color in which noncon-
gruent color words are printed (i.e., interference trial). The
Letter-Number Sequence Test served as a measure of working
memory.11In addition, the Wide Range Achievement Test–
Revised (WRAT-R) measured reading achievement12and served
as a measure of education quality, since years of education has
been shown to be inadequate in measuring the educational expe-
rience of African Americans.13The Center for Epidemiologic
Studies–Depression Scale (CES-D) measured presence of signif-
icant depressive symptoms (i.e., score of 16 or higher).14
Functional MRI procedure. A subset of 22 women partici-
pated in an optional fMRI study, and seven HIV? and four
HIV? women had valid data. Invalid data were due to organic
brain abnormality (n ? 1), incomplete scan data (n ? 2), tech-
nical problems (n ? 2), and below-chance performance on the
behavioral task (n ? 6).
Blood oxygen level dependent fMRI was performed on a
3.0-Tesla whole-body scanner (Excite 2.0; GE Healthcare,
Waukesha, WI). Twenty-four obliqued images prescribed paral-
lel to the plane defined by points of intersection including both
the anterior and posterior commissure were acquired through
the cerebral hemispheres using gradient-echo echoplanar imag-
ing (flip ? 90°, echo time [TE] ? 25 msec, voxel size ?
3.125 ? 3.125 ? 5 mm3, repetition time [TR] ? 1.5 s, 24
slices). A single T1-weighted volume (three-dimensional IRf-
SPGR) was also acquired, plane ? axial, TR ? 9 msec, TE ?
2.0 msec, flip angle ? 25°, number of excitations ? 1, band-
width ? 15.6 kHz, voxel size ? 0.5 ? 0.06 ? 1.5 mm3, slices ?
The fMRI memory test included two tasks—encoding and
recognition—separated by a 20-minute delay during which
structural scans were acquired. The memory test was adapted for
the fMRI environment (e.g., block design, timing of stimulus
presentation) from a PET task used in the Baltimore Longitudi-
nal Study of Aging15with control conditions modeled after other
fMRI studies.16A block design was used with a 3-s stimulus
presentation and 1,500-ms interstimulus interval. The encoding
task included 10 eight-item blocks (total ? 80 stimuli). Blocks
alternated between experimental (5 eight-item blocks for 40
novel words) and control conditions (5 eight-item blocks for 40
repeating stimuli). During both conditions, participants viewed
targets individually on a back-projection screen and grasped a
two-button response unit with the dominant hand. Participants
were instructed to “try to remember each item for a later mem-
ory task” and to indicate that they had seen the item by pressing
the index finger button whenever an item appeared. Participants
were also told that the words “edition” and “region” would be
repeatedly shown. Before entering the scanner, participants com-
pleted practice items to ensure that they understood the task.
Neurology 72May 12, 2009
Experimental blocks included unique, abstract nouns (e.g., sys-
tem, position). Control blocks included repeated presentations
of two abstract nouns (i.e., region, edition). This control condi-
tion places limited demands on memory because of repeated
stimulus exposure, but, like the experimental condition, places
demands on perceptual, motor, and lexical processes.
The recognition task included 20 eight-item blocks (total stim-
uli ? 160) that alternated between experimental and control tasks.
Each experimental block included target stimuli from the encoding
task and distractor stimuli that had not been presented during the
encoding task. Each control block involved the repeated presenta-
tion of “region” and “edition.” The number of target and distractor
items varied across control blocks. During both experimental and
ally on a back-projection screen and indicated whether they recog-
nized the word from the encoding task by pressing the index finger
button for “yes” responses and middle finger button for “no” re-
sponses. The primary outcome was the number correct during the
experimental blocks (max ? 80).
Neuroimaging analysis. We preprocessed and analyzed the
data using Statistical Parametric Mapping (SPM2; Welcome De-
partment of Cognitive Neurology, London, UK) (see table e-1
on the Neurology®Web site at www.neurology.org for a descrip-
tion of preprocessing steps). Data were modeled using a boxcar
function convolved with a canonical hemodynamic response
function and were analyzed using a two-level mixed effects
model (random effect analysis). The WFU Pickatlas17and the
AAL template18were used to define a priori regions of interest
(ROIs), including the primary ROI, which included the hip-
pocampus and parahippocampal gyrus. The PickAtlas small vol-
ume correction was applied during thresholding. Linear
contrasts of the parameter estimates for effects of interest were
obtained for each participant and then entered into a between-
subjects analysis that produced a statistical parametric map of the
t statistic at every voxel within the ROIs. The primary contrasts
of interest were the group differences (HIV? vs HIV?) in the
experimental vs control conditions for the encoding and recogni-
tion tasks. Given the relatively small sizes of the ROIs and corre-
sponding small number of voxel-wise comparisons, group
differences are presented at a p ? 0.05 (uncorrected) threshold
and a minimum cluster size (k) of 30 contiguous voxels. This
conservative cluster size was chosen to reduce the likelihood of
Type II errors. To examine the functional significance of group
differences, we extracted the first eigenvariate of all voxel values
contained in a 3-mm radial sphere around the peak voxel for
each participant and correlated these values with HVLT scores.
Anatomic localization of significant clusters was determined by
converting MNI coordinates to standard Talairach coordinates
using a nonlinear transformation (http://www.mrc-cbu.cam.
ac.uk/Imaging/Common/downloads/MNI2tal/mni2tal.m) and by
consulting brain atlases19,20and the Talairach Daemon.21
RESULTS Cognitive results. HIV? and HIV? par-
ticipants were similar in mean age, years of education,
educational quality as measured by the WRAT-R, race,
and depressive symptoms (table 1). Participants were
86% African American, 5% non-Hispanic white, 8%
Hispanic, and 1% other. Groups differed significantly
of HIV? women, ?2(1) ? 4.91, p ? 0.05, but not on
previous drug use, current or past alcohol use, or cur-
rent smoking. For HIV? participants, the mean CD4
Table 1Participant characteristics as a
function of serostatus
VariablesHIV? (n ? 51)HIV? (n ? 12)
Age, y, mean (SD)
43.37 (6.79)42.92 (5.52)
11.86 (2.34) 12.92 (2.19)
40.75 (8.30)42.83 (7.72)
Recent drug use, %*
Past drug use, %
Recent alcohol use, %
14 or more drinks/wk
History of >14
Current smoking, %
Peak viral load
Current viral load
Neurology 72May 12, 2009
0–1,345), and 22% had AIDS-defining (?200) CD4
Sixty-nine percent were prescribed antiretroviral
therapy at testing, including HAART (61%) and non-
HAART therapy (8%).22Current plasma viral load
was undetectable for 47%, ?10,000 for 25%, and
?10,000 for 28% HIV? participants. The hepatitis C
antibody (HCV) test was positive for 33% of HIV?
and 59% of HIV? women, ?2(1) ? 2.54, NS.
Three sets of analyses were performed on neuro-
psychological outcomes (SPSS 15.0 for Windows,
Chicago, IL). First, t tests were performed to examine
group differences in unadjusted scores. Next, data
were analyzed using a stepwise multivariate regres-
sion with HIV serostatus and recent drug use as pre-
dictor variables. As shown in table 2, in both
adjusted and unadjusted analyses, HIV? women
performed significantly worse than HIV? women
on HVLT immediate and delayed recall, each Rey
outcome, and Letter-Number Sequence subtest, p ?
0.05. Finally, a stepwise multivariate regression with
HIV? women only was conducted using only demo-
graphic and clinical variables that correlated signifi-
cantly with performance. Recent drug use predicted
significantly lower scores on the Stroop Color trial.
Analyses within HIV? women showed no association
between cognitive performance and HAART use.
Higher viral load predicted lower scores on the Rey im-
mediate recall, standardized ? ? ?0.271, p ? 0.05.
Neuroimaging results. HIV? and HIV? women
with valid neuroimaging data did not differ signifi-
cantly in mean age (41.1 vs 42.8 years), education
(11.7 vs 12.3 years), WRAT-R scores (43.9 vs 42.0),
mean percent correct on the fMRI verbal memory
task (63% vs 62%), or frequency of positive HCV
antibody results (57% vs 50%), depressive symptoms
(58% vs 75%), or drug use (29% vs 50%), all p ?
0.53. African Americans comprised 91% of this sub-
sample. Three HIV? women reported being on
HAART. In this subsample, scores on the immediate
HVLT trials were lower in HIV? (mean ? 21.85)
vs HIV? women (29.00), t (9) ? 2.42, p ? 0.05.
Scores on the HVLT delayed trial were also lower
(7.28 vs 8.75), though this was not significant, p ?
0.10. The average lag time between cognitive testing
and MRI was 102 days, and women were scanned
during the follicular phase. In HIV? women, educa-
tional attainment (i.e., WRAT-R score) predicted all
cognitive outcomes. Additionally, depressive symp-
toms predicted verbal learning, verbal delayed recall,
and Rey Copy, and age predicted delayed recall. Re-
cent illicit drug use predicted delayed recall (trend
only) and letter-number sequencing. Disease charac-
Variables HIV? (n ? 51)HIV? (n ? 12)
HAART use, %
Depressive symptoms measured by CES-D scale, with ?16
cutoff. Recent and past drug use were ascertained by self-
report. Recent refers to within 6 months of the most recent
CORE visit.Undetectable viral load levels were fewer than
80 copies as measured by NucliSens test kit.
*?2(1) ? 4.91, p ? 0.05 for group difference in recent drug
†CD4 nadir was the lowest CD4 level to date regardless of
WRAT ? Wide Range Achievement Test; CES-D ? Center
for Epidemiologic Studies Depression; HAART ? highly ac-
tive antiretroviral therapy; ARV ? antiretroviral therapy;
HCV ? hepatitis C virus antibody.
Table 2Performance on behavioral measures of verbal memory and other
cognitive abilities in HIV? and HIV? women: Results from
unadjusted and adjusted group comparisons
Unadjusted group means and
group comparisons, mean (SD)
Total recall trials 1–3
22.45 (5.14)*26.83 (4.97)
7.43 (2.62)†9.08 (2.23)
10.45 (1.59) 10.75 (1.29)NSNS
25.05 (5.34)† 28.71 (2.74)
9.99 (5.12)†13.38 (5.03)
10.25 (4.80)†13.67 (5.80)
10.67 (3.98)†13.42 (3.96)
66.45 (14.98)62.17 (11.16) NSNS
51.59 (11.47)‡44.83 (8.47)0.24‡NS
132.75 (31.45) 121.17 (24.73)NSNS
Drug use included self-reported crack, heroin, or cocaine use since the previous Women’s
Interagency HIV Study visit (i.e., on average within the previous 6 months). Regressions
were run because both serostatus and drug use differed between groups.
*p ? 0.01.
†p ? 0.05.
‡Trend, p ? 0.06.
Neurology 72May 12, 2009
teristics predicted performance only on the inhibi-
tion trial of the Stroop (i.e., highest viral load, trend).
Table e-1 and figure 1 show the results from the
primary contrasts of interest in the hippocampus and
parahippocampal gyrus. For the encoding contrast,
there were no regions where HIV? women showed
greater activation compared to HIV? women. How-
ever, the HIV? group showed greater bilateral acti-
vation in the hippocampus and parahippocampal
gyrus compared to HIV? group. These differences
were particularly pronounced in the left hemisphere
(figure 1). This differential increase in activation by
HIV? group reflects a combination of two influ-
ences: 1) greater activation in HIV? vs HIV?
women during the experimental encoding condition
(i.e., encoding of unique words); and 2) greater acti-
vation in HIV? vs HIV? group during the control
encoding condition (i.e., repeated encoding of the
same two words). In the recognition contrast, there
were no regions where HIV? women showed greater
activation compared to HIV? women. However,
the HIV? group showed greater activation in the
right hippocampus and bilateral parahippocampal
gyrus (figure 2). This differential increase in activa-
tion by HIV? vs HIV? group reflects 1) greater
activation in the right parahippocampal gyrus and
hippocampus in HIV? vs HIV? women during the
experimental recognition condition (i.e., recognition
of unique words) and 2) greater activation in HIV?
women in the left and right parahippocampal gyrus
during the control recognition task (i.e., recognition
of repeated words). In summary, compared to HIV?
Results of primary region of interest analyses. Hippocampal and parahippocampal regions where HIV? women showed
significant (p ? 0.05) increases in activation compared to HIV? women, including (A) glass brain sagittal, coronal, and axial
projections centered on cluster with threshold at Talairach coordinates (?36, ?18, ?11); (B) right hemisphere blood oxy-
gen level dependent (BOLD) signal superimposed on single subject fMRI template at Talairach coordinates (?36, ?18,
?11) at crosshairs; (C) glass brain sagittal, coronal, and axial projections centered on cluster with threshold at Talairach
coordinates (36, ?22, ?12); and (D) left hemisphere BOLD signal superimposed on single subject fMRI template at Ta-
lairach coordinates (36, ?22, ?12) at crosshairs (see also figure e-1, where upper two scatterplots depict the functional
significance of this activation). R ? right hemisphere; L ? left hemisphere.
Neurology 72May 12, 2009
women, HIV? women showed decreased hip-
pocampal activation during encoding and increased
hippocampal activation during recognition.
Table 3 shows the correlations between the mag-
nitude of signal intensity in the hippocampus and
HVLT memory indices. Higher signal intensity in
the left hippocampus during encoding was associated
with better performance on the HVLT (see figure
e-1). Thus, in a hippocampal region where HIV?
women showed less activation compared to HIV?
women, less activation was associated with worse
memory on standardized tests. Higher signal in-
tensity in the right hippocampus during recogni-
tion was associated with worse performance on the
HVLT (see figure e-1). Thus, in a hippocampal
region where HIV? women showed more activa-
tion compared to HIV? women, more activation
was associated with worse memory. There were no
correlations between hippocampal activation and
performance on the scanner task (r range ?0.38 to
0.15, all p ? 0.24).
We also conducted a post hoc, exploratory whole-
brain analysis, using a more conservative threshold of
p ? 0.01, a minimum cluster size of 30 voxels, and
an uncorrected cluster threshold of p ? 0.05 (see
table e-2). For the encoding contrast, significantly
greater activation was evident for HIV? vs HIV?
women in clusters including (A) right middle tempo-
ral cortex, parahippocampal gyrus, and hippocam-
pus; (B) left parahippocampal gyrus, middle
temporal cortex, and hippocampus; and (C) right su-
perior frontal gyrus. For that same contrast, HIV?
Figure 2 Greater activation in the hippocampus and parahippocampal gyrus in HIV? vs HIV? women during
recognition of unique words (experimental condition) minus repeated recognition of the same
two words (control condition)
Neurology 72May 12, 2009
vs HIV? women showed more activation in the
right posterior cerebellum. For the recognition con-
trast, HIV? women vs HIV? women showed
greater activation in (A) right and left prefrontal cor-
tex and (B) right precuneus, whereas HIV? vs
HIV? women showed greater activation in (A) left
superior temporal gyrus and hippocampus and (B)
right insular cortex. Thus, both the exploratory and
ROI analyses indicate hippocampal dysfunction.
DISCUSSION The aim of this preliminary study was
to investigate the integrity of episodic memory and pat-
terns of neural activation during performance of a
infected and at-risk, HIV? women. The cohort was
86% African American, frequently used illicit drugs,
and had low socioeconomic status and low quality of
education. In unadjusted analyses and analyses adjust-
ing for drug use, HIV? women vs HIV? women
showed deficits in verbal learning, verbal delayed recall
on the HVLT, visuoconstructional abilities, figural epi-
sodic memory, and working memory. Neuroimaging
results indicated that compared to the HIV? group,
the HIV? group showed decreased hippocampal acti-
vation during encoding and increased hippocampal ac-
tivation during recognition. The magnitude of
the HVLT. The direction of these correlations indi-
cated that underactivation of left hippocampus during
encoding and overactivation of the right hippocampus
during retrieval were associated with worse memory on
gest that HIV might affect the functional integrity of
medial temporal systems underlying verbal memory
Although HIV? vs HIV? men perform worse
on the HVLT,23most previous neuropsychological
investigations have found little evidence of impair-
ments in episodic verbal memory in HIV?
women.24-28Comparisons with the present study are
limited by sample sizes of less than 45 women24,25
and the use of factor scores26or dichotomous im-
paired vs unimpaired scores27,28as outcomes. The
fMRI findings provide insights into the neurobiolog-
ical underpinnings of the verbal memory impairment
observed on the HVLT, because the fMRI task, like
the HVLT, comprised a verbal encoding task, fol-
lowed by a delayed retrieval task 20 minutes later.
HIV? women showed decreased activation of the
hippocampus and parahippocampal gyrus during
verbal encoding, particularly in the left hemisphere.
These findings parallel findings where HIV? vs
HIV? men showed decreased activation in the right
parahippocampal gyrus during encoding of scenes, a
task that relies more heavily on the right hemi-
sphere.5Our finding of overactivation of the hip-
pocampus during recognition in HIV? women
argues against the view that hippocampal damage is
producing a universal decrease in activation across
tasks. Nevertheless, replication of the findings, par-
ticularly the neuroimaging findings, is important be-
cause the sample size was limited and six women
were excluded for below-chance performance. Also,
although fewer HIV? vs HIV? women reported re-
cent illicit drug use, among HIV? women there was a
The lower rate of recent drug use among HIV?
women is probably related to more treatment options
and attention to drug use within HIV care settings. Fu-
ture larger studies should investigate the individual and
interactive effects of HIV infection and drugs of abuse
on hippocampal function. Future studies should also
focus on the possibility that the hippocampus contrib-
utes to the disruption of a larger neural network that
drives HIV-associated memory impairments.
This work was supported by NIH/NIAID grant U01-AI-34993, the Chi-
cago Consortium Women’s Interagency HIV Study, to Mardge Cohen,
MD (PI). Chicago WIHS is cofunded by the NCI and NIDA. Dr. Maki
has received grant support from the National Institute on Allergy and
Infectious Disease (NIAID), National Center on Complementary and
Alternative Medicine, Soy Health Research Board, and Wyeth Ayerst. Dr.
Maki has also received honorarium from the National Institutes of Health
(NIH), Soy Research Foundation, Northwestern Memorial Hospital, the
North American Menopause Association, Wyeth Pharmaceuticals,
Fanizzi Associates, and Genaera Corporation. Dr. Cohen and Kathleen
Weber received grant support from the NIAID and the National Institute
on Mental Health (NIMH). Dr. Little has received research grants from
the National Institute on Aging, NIMH, Congressionally Directed Med-
ical Research Program, Department of Defense, and the Chicago Institute
for Neuroscience and Neuroresearch. Dr. Little has also received hono-
raria from the Centre for Neuroskills and serves on the advisory board of
the Sarah Jane Brain Foundation. Leah Rubin received NIH grant sup-
Table 3Correlations between activation levels within significant clusters and
scores on the Hopkins Verbal Learning Test
Condition, group contrastk
Encoding minus control
HIV? > HIV?
HIV? > HIV?
Positive x values indicate left hemisphere activation.
*p ? 0.01.
†p ? 0.05.
‡Trend, p ? 0.10.
HVLT ? Hopkins Verbal Learning Test.
Neurology 72May 12, 2009
port from the NIMH. Dr. Gould received grant support from the Univer-
sity of Miami Developmental Center for AIDS Research (D-CFAR) and
National Institute on Child Health and Human Development. Dr. Mar-
tin has received grant support from the NIAID, National Institute on
Drug Abuse, Veterans Administration Merit Review Board, Glaxo-
Wellcome, University of Illinois Campus Research Board, and University
of Illinois Center for Research on Women and Gender. Dr Martin has
received honorarium from the NIH, University of California-San Diego,
San Francisco VAMC, and the Michael Smith Research Foundation.
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