HIV-positive females show blunted neurophysiological responses in an emotion–attention dual task paradigm

Clinical Neurophysiology 125 (2014) 1164–1173

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Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph

HIV-positive females show blunted neurophysiological responses in an emotion–attention dual task paradigm Jaime L. Tartar a,⇑, Roger C. McIntosh b, Monica Rosselli b, Susan M. Widmayer c, Allan J. Nash b a

Division of Social and Behavioral Sciences, Nova Southeastern University, Ft. Lauderdale, FL, USA Department of Psychology, Florida Atlantic University, Davie, FL, USA c Children’s Diagnostic and Treatment Center, Ft. Lauderdale, FL, USA b

See Editorial, pages 1075–1076

a r t i c l e

i n f o

Article history: Accepted 16 September 2013 Available online 1 December 2013 Keywords: Emotion ERP Female Late positive potential HIV Neuropsychology

h i g h l i g h t s  We tested emotional pictures on subsequent attention processing in HIV+ & HIV

women.

 Unlike healthy controls, HIV+ women do not show electrophysiological markers of intermodal affec-

tive priming.  This study is the first to provide physiological evidence that attention to emotionally-charged visual

stimuli is reduced in HIV-infected individuals.

a b s t r a c t Objective: Although HIV is associated with decreased emotional and cognitive functioning, the mechanisms through which affective changes can alter cognitive processes in HIV-infected individuals are unknown. We aimed to clarify this question through testing the extent to which emotionally negative stimuli prime attention to a subsequent infrequently occurring auditory tone in HIV+ compared to HIV females. Methods: Attention to emotional compared to non-emotional pictures was measured via the LPP ERP. Subsequent attention was indexed through the N1 and late processing negativity ERP. We also assessed mood and cognitive functioning in both groups. Results: In HIV females, emotionally negative pictures, compared to neutral pictures, resulted in an enhanced LPP to the pictures and an enhanced N1 to subsequent tones. The HIV+ group did not show a difference in the LPP measure between picture categories, and accordingly, did not show a priming effect to the subsequent infrequent tones. Conclusions: The ERP findings, combined with neuropsychological deficits, suggest that HIV+ females show impairments in attention to emotionally-laden stimuli and that this impairment might be related to a loss of affective priming. Significance: This study is the first to provide physiological evidence that the LPP, a measure of attention to emotionally-charged visual stimuli, is reduced in HIV-infected individuals. These results set the stage for future work aimed at localizing brain activation to emotional stimuli in HIV+ individuals. Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction ⇑ Corresponding author. Address: Nova Southeastern University, Farquhar College of Arts and Sciences, Division of Social and Behavioral Sciences, 3301 College Avenue, Fort Lauderdale, FL 33314, USA. Tel.: +1 9542628192. E-mail address: [email protected] (J.L. Tartar).

The human immunodeficiency virus (HIV) is associated with decreased emotional and cognitive functioning (Bungener et al., 1995; Morrison et al., 2002; Polich et al., 2000; Reger et al., 2002). However, the mechanisms through which affective changes

1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.09.048

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can alter cognitive processes in HIV-infected individuals are unknown. For example, although depression is prevalent in 40–50% of patients with HIV-associated dementia, the extent to which these conditions influence each other is uncertain (Rabkin et al., 2000). It is difficult to untangle the influence of emotional dysfunction on cognitive impairment because mild cognitive impairment is recognized as a manifestation of emotional disorders and, conversely, emotional dysfunction can also be a chief symptom of cognitive impairment (Kaplan and Sadock, 1998). Depression, apathy, and anxiety are especially prevalent with HIV-infection (Bing et al., 2001; Tate et al., 2003). It is possible that the primary emotional disturbances in HIV are associated with decline in the cognitive domain, such as psychomotor slowing and memory impairments (Owe-Larsson et al., 2009). Typically, emotional disturbances (e.g., apathy, depression) occur early on in the disease followed by HIV-associated cognitive disorders which then increase with disease progression with mild to moderate cognitive disorders occurring in approximately 60% of patients and severe cognitive disorders occurring in 2–8% of patients (McArthur et al., 2010). Issues surrounding quality of life in emotion and cognitive functioning are especially significant for HIV-infected females since they are four times more likely to have depression and show significantly higher anxiety symptom scores compared to HIV-negative females (Morrison et al., 2002). HIV-infected African–American women are a particularly vulnerable population; the rate of infection for this group is 4 and 15 times higher than in Hispanic and Caucasian women, respectively (Lee and McKenna, 2007). For these reasons, we specifically tested HIV-infected females who were predominantly African–American. We used electroencephalographic (EEG) event related potentials (ERPs) due to their precise temporal resolution of brain processes and their great promise in explaining patterns of cortical reactions to emotional visual stimuli (Olofsson et al., 2008). In particular, studies which have used ERPs to understand emotional processing show that compared to non-emotional pictures, emotional pictures garner greater attention resources with negative pictures being more effective than positive pictures at capturing attention resources (Crawford and Cacioppo, 2002; Ohman and Mineka, 2001; Olofsson et al., 2008; Schupp et al., 2004; Smith et al., 2003). The late positive potential (LPP) component of the visual ERP is specifically established as a sensitive measure of attention to emotionally-charged visual stimuli – especially emotional stimuli of negative valence (Cuthbert et al., 2000; Keil et al., 2002; Olofsson and Polich, 2007; Schupp et al., 2000). Induction of the LPP it thought to serve as a neurobiological correlate of motivated attention to stimuli of adaptive significance (sex, death, etc.). In other words, because these stimuli are inherently arousing, they require the preferential allocation of limited attention resources (Lang et al., 1997a). In support of this idea, evidence suggests that the LPP is involved in memory formation for emotional events (Dolcos and Cabeza, 2002). Accordingly, we measured the extent to which emotionally negative compared to emotionally neutral pictures elicited a LPP in HIV+ females. Since cognitive processes indexed by the LPP are shown to alter attention resources in a subsequent task (Keil et al., 2007; Meinhardt and Pekrun, 2003; Tartar et al., 2012), we also assessed the impact of the emotional picture on the processing of a secondary auditory task. Our previous work, which used the same experimental paradigm used here, demonstrated that in healthy college students, emotionally negative stimuli prime attention (indexed through the N1 and late processing negativity ERP) to a subsequent infrequently occurring auditory tone (Tartar et al., 2012). We predicted that, consistent with previous studies showing emotional blunting in HIV individuals, there would be no LPP difference (emotional response) between emotional and nonemotional pictures in the HIV+ group. Since our previous find-

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ings in college students showed that an enhanced LPP to the negative pictures was associated with primed attention for a subsequent infrequently occurring auditory stimulus, we further predicted that a blunting of the LPP in the HIV+ group to emotional picture exposure would result in no priming response to a subsequent tone. We further hypothesized that, consistent with our findings in healthy college students, the HIV control group would show an enhanced LPP on emotional compared to non-emotional picture trials and that the emotional processing would lead to enhanced attention to subsequent infrequently occurring tones. An additional goal of the study was to compare neuropsychological functioning in the participants. To that end, we sought to determine the extent to which measures of mood and cognitive function (executive functioning, motor functioning, and processing speed & language functioning) differ between groups. In addition, we added anxiety as fixed covariate in an attempt to account for the differences in LPP between groups and conditions. 2. Methods 2.1. Participants A total of 35 women were recruited for the study of which 9 participants were excluded due to excessive movement artifact during EEG testing or a score below 24 on the Mini Mental State Exam. Of the remaining 26 participants, the clinical group consisted of 12 right handed asymptomatic HIV+ females (Mage = 37.0 years; SD = 5.72) and the control group consisted of 14 right handed HIV females (Mage = 37.1 years, SD = 6.72). The clinical group was recruited with flyers posted at an outpatient clinic and the control group was recruited with flyers as friends and family of the HIV+ group. Negative HIV status was determined through administration of a rapid-response Orashure™ screening for the HIV virus antibodies. For the purpose of this study, the HIV+ clinical group was characterized by asymptomatic and symptomatic non-AIDS conditions, with a T-cell count greater than 200. Exclusion criteria included previous diagnosis of psychosis and/or history of neurological impairment not stemming from HIV infection. The two groups did not differ in education level (HIV+ = 11.3 years, SD = 3.43; HIV = 11.9 years, SD = 1.44). 20 of the participants were African American, 3 were Hispanic, 2 were White and 1 as self-classified as Other. These 26 participants were fluent in English and scored within the normal range of 25–30 on the Mini Mental State Exam (MMSE). At the conclusion of the study, all participants received a $50 gift card to a local department store, a $10 meal voucher for a local restaurant, and a $10 gas card for transportation. All participants were treated in accordance with APA ethical standards for the use of clinical participants and the protocol was approved by the independent review boards of the contributing institutions. 2.2. EEG data acquisition and analysis EEG assessment was conducted using Contact Precision Instruments’ Psylab EEG amplifying and recording equipment. Scalp electrodes were attached with electrode paste at Fz, Cz, Pz, C3, and C4 in accordance with the International 10–20 System and as previously described (Tartar et al., 2004). Signals were referenced to electrodes attached to earlobes. Electrode impedance was maintained at less than 5 kO. Procedures for infection control specified by the society for psychophysiological research were followed in attaching and removing electrodes (Putnam et al., 1992). The EEG amplifier was set at a gain of 30,000 and the sampling rate of the EEG was 500 Hz. High pass filters were set to. 1 Hz and low

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pass filters were set to 40 Hz and a 60 Hz notch filter was active. The data were analyzed offline through the use of Psylab8 software (Contact Precision Instruments, Cambridge, MA). For the purposes of data analysis, and to maximize the number of artifact free trials, the visual and auditory ERPs were separately baseline corrected and analyzed. 1000 ms of raw EEG data were epoched to the respective stimulus presentation including 100 ms of pre-stimulus baseline in each modality. The LPP was measured as the average voltage 300–800 ms following picture onset and N1 was measured as the peak amplitude 75–150 ms following tone onset. Trials in which the EOG exceeded ±75 mV were excluded from the final averaged ERP. Seventy trials were presented for which an image was presented before the oddball tone. There was no significant difference in the number of artifact-free trials from the HIV women (M = 47.2, SE = 2.89) compared to HIV+ women (M = 49.7, SE = 1.4) F(1, 24) = 0.62, p > .05). 2.3. Stimuli and procedure A dual sensory modality EEG ERP paradigm was employed in which visual ERPs were elicited from participants while they viewed a subset of negative and neutral pictures selected from the International Affective Picture System (IAPS) (Lang et al., 1997b). The IAPS pictures are standardized along the dimensions of arousal and valence and are widely used in studies of emotion and attention (Mikels et al., 2005). Subsequent to picture presentation (600 ms after the picture tuned off), auditory ERPs were elicited through the use of oddball and standard tones in an auditory oddball paradigm. Picture presentation and timing were controlled through the use of Presentation software (Neurobehavioral Systems, LLC). The auditory stimuli (sinusoidal tones) consisted of either 1000 Hz low pitch tones or 2000 Hz high pitch tones. The low pitch tones were used as the standard tones and the high pitch tones were used as the oddball tones. The stimulus intensity was 70 dB and was 100 ms in duration. The IAPS normative ratings (Lang et al., 1997b) were used to select the emotional category of each picture. All participants viewed the same picture set and, due to the high number of trials (350), it was necessary to repeat ten of the pictures one time throughout the paradigm. However, all analyzed (rare) trials contained pictures that had never been shown prior to that trial and did not repeat on any other rare tone trial. In the context of the entire experiment, repeated exposure to the pictures is not expected to alter the affective response. In particular, Smith et al. (2005) presented IAPS pictures six times in one experiment with no reported effect of picture repetition on ERP responses. The average negative picture normative rating was 2.32 (SD = 0.69) and the average neutral picture normative rating was 4.94 (SD = 0.62). 2.4. Trial description There were 350 trials which were broken up into 7 blocks of 50 trials to allow for short (about 2 min) breaks for the participants during the experiment. Fig. 1 depicts a visual representation of the experimental trials. Each trial lasted 1200 ms and began with a 200 ms randomized presentation of either a negative (n = 175, 50%) or neutral (n = 175, 50%) picture. All pictures were presented on a 23-inch LCD monitor with a vertical refresh rate of 60 Hz; the pictures flickered 12 times during the 200 ms duration. A central fixation point was present in the center of the screen throughout the experiment. We chose emotionally negative stimuli as the visual prime since, compared to appetitive (or pleasant) stimuli, emotionally negative (or unpleasant) stimuli typically produce stronger emotional responses (Crawford and Cacioppo, 2002; Ohman and Mineka, 2001; Schupp et al., 2004; Smith et al., 2003). Following the picture presentation, the participants viewed

a black screen with a fixation point which was on for the rest of the trial. A tone was presented 600 ms following the picture which consisted of randomized presentation of an oddball (n = 70, 20%) or a standard (n = 280, 80%) tone. The frequency of oddball and standard tone was split evenly between negative and neutral picture categories so that oddball tones occurred on 10% of neutral picture trials and 10% of negative picture trials. In order to insure that the participants attended to both the picture and tone categories and to index behavioral responses to the picture and tone categories, the participants were instructed to categorize each picture-tone combination on a computer keyboard at the end of each picture-tone trial. Possible combinations included a negative picture followed by an oddball tone, a negative picture followed by a standard tone, a neutral picture followed by an oddball tone, or a neutral picture followed by a standard tone. Participants were given 3000 ms to categorize the picture tone combination before the trials began. Participants were given a practice session with non-experimental pictures until they memorized and were comfortable with the procedure, the categorization task and the timing of the trial. 2.5. Neuropsychological battery Following the EEG session, electrodes were removed and participants were given a 15 min break before being administered a neuropsychological test battery. This testing consisted of a 1 h block of neurometric testing for which the order of the tests was randomized. These tests included the Mini Mental State Exam (MMSE) (Folstein et al., 1975) which is a test on the cognitive aspects of mental state. Visual naming ability was assessed with a shortened 15-item version of the Boston Naming Test (BNT; Kaplan and Sadock, 1998), Fine motor speed and eye-hand coordination was assessed through the use of two tasks Grooved Pegboard Test (GPT; Trites, 1989) and Finger Tapping Test (FTT; Reitan and Wolfson, 1993). Executive function was measured through by the Trail Making Test Part A and B (TMT A/B; Reitan and Wolfson, 1993) and the Controlled Oral Word Association Test (COWAT; Spreen and Strauss, 1998). Also processing speed was measure by using a letter-comparison task. Three measures of mood were also included in the analysis in order to examine the extent to which the continuous scores on these measures co-varied with ERP measures. This included the State Trait Anxiety Inventory (STAI; Spielberger, 1984), Beck Depression Inventory (BDI-II; Beck et al., 1988), and a 40-item Multidimensional Quality of Life scale for persons with HIV (MQOL-HIV; Smith et al., 1997). 2.6. Statistical analyses To examine the effect of picture category and serostatus on the visual LPP we carried out a 2  2  3 general linear model (GLM) with repeated measures (RM). The within-subject factors were picture category (negative vs. neutral) and midline electrode locations (Fz, Cz, Pz). The between-subjects factor was serostatus (HIV+ or HIV ). To examine the effects of picture category, serostatus and electrode locations on auditory ERPs we performed two additional 2  2  3 general lineal models (GLM) with repeated measures for the N1 and late processing negativity ERP auditory dependent measure. GLM analyses include a measure of partial g2 as effect size. Following all significant effects and interactions, post-hoc pairwise comparisons were carried out using a Bonferonni adjustment for multiple comparisons. The topic of depression prevalence rates in HIV is fraught with methodological limitations such as sampling selection, co-morbidities, heterogeneity of self-report scales, and use/exclusion of structured clinical interviews (Rabkin, 2008). Thus, elevated reports of depressive symptoms between

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Fig. 1. Trial depiction. Each trial began with either a negative or a neutral picture – each of which occurred on 50% of the trials. 600 ms following picture exposure, participants received an auditory stimulus which was either an oddball (occurring on 20% of the trials) or a standard (occurring on 80% of the trials) tone. The frequency of oddball and standard tones was split evenly between negative and neutral picture categories so that oddball tones occurred on 10% of the neutral picture trials and 10% of the negative picture trials. Participants were instructed to rate (keyboard press) the picture and tone category from that trial immediately after hearing the tone.

HIV+ and HIV women have been shown by some (Morrison et al., 2002) but not others (Moore et al., 1999). Accordingly, we were interested in determining the extent to which measures of depressive and anxious symptomotology related back to any observed emotional or cognitive deficits. To this end, an analysis of covariance for trait anxiety and depressive symptomology was conducted on all main effects and interactions found within individual ERP component analyses. In addition to the ERP analyses, we also carried out a series of ttests on the behavioral responses to the picture and tone categorization procedure with Cohen’s d as the calculated effect size. In these analyses, we measured reaction time to categorize the picture-tone combination (measured as the latency to respond following tone onset). We also carried out between-groups ANOVA to detect if there was a difference between groups on the percentage of pictures that were categorized as negative vs. neutral, as well as the IAPS normalized valence ratings of those images. All calculations were conducted using an SPSS statistical package (version 19, SPSS Inc., IBM Company). In instances where the sphericity assumption was not met, the reported p-values associated with the F statistics are adjusted via Greenhouse-Geisser. All reported p values are two-tailed with an a priori significance level of p < 0.05. 3. Results 3.1. Emotional picture processing: visual LPP analyses Fig. 2 shows the visual ERPs for both groups. There was a main effect for picture valence (F(1, 24) = 6.75, gp2 = 0.22, p < 0.05) for the visual LPP ERP. Bonferroni correction showed that the average LPP was significantly larger for the negative condition (M = 3.58, SE = 0.72) compared to neutral picture condition (M = 2.04, SE = 0.66), p < .05. The HIV status  valence interaction was also significant (F(1, 24) = 5.38, partial g2 = 0.18, p < 0.05). The 2-way interaction was decomposed using multivariate tests and revealed simple effects for picture valence across electrodes within the HIV group (F(1, 24) = 11.23, gp2 = 0.32, p < 0.01), but not HIV+ positive group (p > 0.05). Consistent with our previous findings in a non-clinical population, we found that the HIV women demonstrated a significantly larger LPP to negative (M = 4.44, SE = 1.05)

compared to neutral (M = 1.52, SE = 0.96) IAPS images. Multivariate simple effects for picture valence were found for HIV women at the Cz (p < 0.05) and Pz (p < 0.001) electrode locations. There was no difference in the LPP amplitude between picture categories in the HIV+ group. In addition, the LPP for negative images (M = 2.27, SE = .97) did not differ from neutral images (M = 2.56, SE = .89) for the HIV-negative group. Since visual inspection of the LPP suggested that the group differences in valence could have been due to differences in the processing of the neutral pictures, we conducted an additional analysis to ensure that our effects were not due to increased LPP’s to the neutral stimuli in the HIV group compared to HIV+ group. This post-hoc ANOVA was not significant F(1, 24) = .04, p = .84, eta-squared = .002. Finally, there was a three-way interaction present, F(2, 48) = 6.80, gp2 = 0.22, p < 0.01). Visual inspection of the graph demonstrates the HIV  valence interactions was more pronounced at central-parietal electrode locations than frontal-central electrode locations. 3.2. Subsequent attention effects: auditory N1 and processing negativity measures Fig. 3 shows the auditory ERP measures for both groups. For the auditory ERP, there was no main effect for picture valence (F(1, 24) = 1.81, gp2 = 0.70, p > 0.05); however, the HIV-status  valence interaction was significant (F(1, 24) = 6.31, gp2 = 0.21, p < 0.05). The 2-way interaction was decomposed using multivariate tests and revealed simple effects for picture valence across electrodes for the HIV group (F(1, 24) = 6.91, gp2 = 0.22, p < 0.05) but not the HIV+ group (p > 0.05). Consistent with our previous findings in a non-clinical population, the HIV women demonstrated a significantly larger N1 following the presentation of negative (M = 9.83, SE = 0.82) compared to neutral (M = 7.92, SE = 0.56) IAPS images. Multivariate simple effects for picture valence on N1 amplitudes were found for HIV women at the Fz (p < 0.05) and Cz (p < 0.05) and marginally for Pz (p = 0.05) electrode locations. There was not the case for the HIV+ group who did not show a difference in the N1 following a negative compared to neutral picture. Finally, unlike our previous findings in a non-clinical population, we did not observe extended or processing negativity

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Fig. 2. Visual LPP ERPs. HIV (left side) and HIV+ (right side) were exposed to an emotionally negative or neutral picture for 200 ms (black bar on x axis). Visual ERP LPP analyses showed that compared to emotionally neutral picture trials, negative picture trials resulted in a larger visual late positive potential (LPP) at Cz and Pz electrode locations for the HIV group, but not the HIV+ group. Light gray boxes depict the analyzed latency range for the LPP.

in the HIV pictures.

group following negative compared to neutral

3.3. Neuropsychological data One-way ANOVAs were performed to determine whether HIV status had an effect on motor functioning, language functioning, information processing speed and executive skills (see Table 1). HIV+ women had a significantly lower finger-tap score with both dominant and non-dominant hands and a significantly lower Grooved PegBoard score with the dominant hand than HIV females; longer non-dominant time than HIV females; as well as longer time of completion on the Trails-A. Pertaining to seman-

tic verbal fluency, HIV+ women generated significantly less categorical words than HIV females The test of information processing speed demonstrated that HIV+ women had a significantly slower speed of processing; SER and neuropsychological correlates. 3.4. Neuropsychological and ERP interactions A repeated measures analysis of covariance (ANCOVA) was conducted for this study in an effort to account for the effects of depressive and anxiety symptomology on the interaction of serostatus with valence & electrode location. When accounting for self-report depressive symptomology, the interaction between

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Fig. 3. Auditory ERPs. The auditory ERPs were separately analyzed by the preceding picture (negative vs. neutral) classification. In the HIV group (left side), analyses of the oddball tone trials showed that there was greater attention (enhanced N1) to the tones when participants saw a negative picture then heard and oddball tone compared to when the participants saw a neutral picture then heard an oddball tone. The HIV+ group did not show this priming effect. In fact they showed the opposite pattern – there was an enhanced N1 to the tones that were precede by a neutral picture. Light gray boxes depict the analyzed latency range for the late processing analyses.

HIV-group and picture valence remained significant F(2, 23) = 4.32, p < 0.05, gp2 = 0.16. Moreover, the three-way interaction also remained significant F(2, 46) = 5.81, p < 0.05, gp2 = 0.20. The analysis of covariance explained by self-report ratings of anxiety appeared to drive the HIV-group  picture valence interaction to a level of trending significance, F(1, 23) = 3.97, p = 0.058, gp2 = 0.15. The three-way interaction did, however, remain significant when accounting for anxiety F(2, 46) = 6.53, p < 0.01, gp2 = 0.22. As with the late slow wave, a repeated measures ANCOVA was also used to account for self-report differences in depressive and

anxiety symptomology on the magnitude of the N1. The two-way interaction between serostatus and picture valence was first specified in this covariate model. The analysis indicated that the relationship between serostatus and picture valence did not vary the N1 amplitude as a function of anxiety symptomology, F(1, 23) = 5.40, p < 0.05, gp2 = 0.19, but did vary as a function of depressive symptomology, reducing the significance level to marginal F(1, 23) = 3.92, p = 0.06, gp2 = 0.15. Altogether, trait anxiety appeared to have a greater effect on differences in the affective visual-ERP response, whereas depressive symptoms explain some variance in

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Table 1 Group differences for demographic and neuropsychological test performance. Variable name

Age (years) Education (years) Mini Mental State Exam Finger Tapping (dominant) Finger Tapping (non-dominant) Processing speed Grooved PegBoard (dominant) Grooved PegBoard (non-dom) Phonemic fluency Semantic fluency Trail Making Test A Trail Making Test B Trail Making Test B – A Boston Naming Task State anxiety Trait anxiety Depression

HIV status HIV(+)

HIV( )

37.0 (5.72) 11.3 (3.43) 26.7 (2.87) 32.6 (10.9) 32.4 (7.88) 2.90 (1.04) 88.8 (28.4) 101.2 (33.3) 31.8 (14.8) 24.8 (3.85) 46.3 (14.8) 89.8 (34.7) 43.5 (26.2) 10.6 (1.85) 32.9 (10.1) 40.9 (10.6) 13.7 (9.31)

37.1 11.9 28.3 43.0 39.1 1.90 67.6 80.3 40.3 32.3 33.2 69.3 36.2 12.6 31.8 33.8 7.17

(6.71) (1.44) (1.26) (7.39) (6.33) (0.54) (16.8) (22.6) (12.4) (8.08) (10.9) (17.6) (14.3) (1.83) (11.7) (7.78) (5.54)

F

gp 2

0.00 0.35 2.97 7.56** 5.491* 4.50 5.03* 3.34 2.41 9.16** 6.29* 3.39 0.74 6.39* .058 3.70 4.43*

0.00 0.01 0.11 0.25 0.19 0.27 0.18 0.13 0.10 0.29 0.22 0.13 0.03 0.23 0.00 0.13 0.16

Note: Standard deviations appear in parentheses beside raw mean scores. p < .05. p < .01.

*

**

the early auditory oddball response. A series of correlational analyses were conducted to compare the magnitude of change in LPP amplitude with neuropsychological performance in multiple cognitive domains. Two of three executive skills measures (SFL and Trails-B) demonstrated a moderate correlation with a change in LPP such that a shorter time of completion for the trail making time, (r(25) = .457, p = .02) and higher semantic verbal fluency score, r(25) = .698, p < .0001) were associated with a larger magnitude of change from neutral to negative picture viewing. The magnitude of spontaneous emotional response operationalized as previously described was also inversely correlated with Grooved Pegboard time of completion for dominant r(25) = .455, p = .022; and non-dominant hands r(25) = .433, p = .031.

3.5. Behavioral response As a manipulation check participants were asked to respond to the visual and auditory trial stimuli by categorizing the nature of the picture (neutral vs. negative) and tone (oddball vs. standard). A 2  2 repeated measures ANOVA was used to compare response latency between groups for correctly identifying the stimuli following neutral vs. negative pictures. The analysis revealed no significant effect for valence on response latency (p > .05). The interaction between picture valence and serostatus was also not significant at the .05 level F(1, 25) = 2.63, p = .11. This suggests that there was little or no difference in response latency for tones primed with neutral (M = 1.00, SD = .14) and negative IAPS (M = .99, SD = .16) in the seronegative group as well as the neutral (M = 0.96, SD = .20) and negative IAPS (M = 0.96, SD = .23) in the HIV+ group. The average valence of IAPS images categorized as negative were not significantly different between HIV+ (M = 1.74, SD = .09) and HIV women (M = 1.75, SD = .07), F(1, 24) = .04, p > .05). There was also no statistical difference, F(1, 24) = 3.54, p > .05), present between HIV+ (M = 4.67, SD = .13) and HIV women (M = 4.75, SD = .06), in the IAPS-normed ratings of the images which they classified as neutral.

4. Discussion 4.1. General discussion The present study tested the extent to which emotional pictures can prime attention resources for a subsequent auditory stimulus in HIV+ compared to age- and SES-matched HIV women. Consistent with previous LPP literature, the HIV group showed an enhanced LPP to emotionally negative stimuli. However, new to our study, we find that emotional pictures do not elicit an enhanced LPP in HIV+ women. This suggests that the emotional pictures did not garner greater attention resource allocation than the emotionally neutral pictures (Lang et al., 1997a) and is consistent with findings of behavioral emotional apathy in HIV (Bing et al., 2001; Tate et al., 2003). Importantly, the finding that in the HIV group motivational engagement to the negative pictures (measured through enhanced LPP) primes attention resources for a subsequent salient intermodal stimulus (an oddball tone) are consistent with our previous findings in college students. In support of this idea, we find that in the HIV+ group, a lack of a motivational engagement to the negative pictures prevents the priming effect to the subsequent tone. 4.2. Motivational engagement to the pictures: LPP Previous work consistently shows that the LPP is larger after viewing emotional stimuli compared to neutral stimuli (Dunning and Hajcak, 2009; Flaisch et al., 2008; Hajcak et al., 2009; Hajcak and Olvet, 2008; Keil et al., 2002; Muhlberger et al., 2009; Pastor et al., 2008) and can be thought of as an index of motivational engagement or recruitment of attentional resources to the emotional stimuli (Bradley et al., 2007). Here, a blunting effect was found in the HIV+ group in that the LPP response to the emotional pictures was not greater than it was to the neutral pictures. It is possible that this LPP attenuation is related to HIV-associated neural deficits in LPP generators. The central-parietal recorded LPP is thought to reflect aggregate activity across the visual cortex governed by subcortical limbic and cortical structures involved in stimulus orientation, attention, and subsequent action (Sabatinelli et al., 2013). Accordingly, reduced cortex volume reported with HIV-infection potentially explains the loss of an LPP response here (Thompson et al., 2005). fMRI work with emotional picture viewing in HIV+ compared to HIV individuals will be useful in localizing possible neural deficits in emotional processing. Independent of CNS involvement, it has also been argued that emotional deficits in HIV+ individuals might serve an adaptive function in the course of disease progression (Bungener et al., 1995). In this view, volitional emotional blunting serves to protect the individual against the threatening consequences of living with HIV. Alternatively, pre-existing differences in affect and mood are another potential source for the group difference in LPP amplitudes to emotional pictures. Enhanced LPP amplitudes are associated with higher levels of state anxiety (MacNamara and Hajcak, 2009) and reduced LPP amplitudes are associated with increased apathy (Dietz et al., 2013). However, we did not see any effects here of anxiety symptomatology on LPP measures. 4.3. Primed attention effects: N1 and processing negativity An additional aim of this study was to demonstrate that, consistent with our previous findings, emotional pictures prime attention to a subsequent oddball tone. We did not look at standard tones trials here since our previous work shows that the priming effects are more robust for oddball compared to standard tone trials. We observed increased attention to oddball tones following the pre-

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sentation of negative, but not neutral pictures in the HIV control group. This was not the case in the HIV+ group; this group did not show an enhanced LPP to the emotional images, and subsequently, did not show an enhanced N1 to the subsequent tone, supporting the idea that that LPP generation is necessary for attentional enhancement to the subsequent auditory stimuli. However, the HIV+ group did show an enhanced N1 to the tones following a neutral picture. It is not clear if this increase in attention to the tones after neutral compared to emotional pictures is related to the reduced attention (no LPP) to emotional pictures. The lack of an enhanced N1 in the HIV+ group following emotional pictures is likely due to a lack of priming and not an HIV-associated decrease in N1 amplitude since HIV+ individuals show characteristic N1 amplitudes in an auditory-oddball paradigm (Handelsman et al., 1992; Tartar et al., 2004) and following neutral pictures in the present study. Furthermore, the auditory N1 is shown to be relatively robust across the lifespan, and is resilient even to age-related dementia (Anderer et al., 1998). Unlike our previous findings, we did not observe enhanced processing negativity in the HIV group, suggesting that the emotional priming effect of the pictures was not as robust as it was in the previous study. Since the HIV women showed normal neuropsychological test performance in several domains, it is unlikely that the neurocognitive ability could be implicated in the apparent deficit in late processing negativity. It is possible that the emotional pictures had a greater motivational relevance for the college student population compared to the HIV group in the present study. This is reflected in the behavioral response data as well; the college students in our previous study showed faster response times to the oddball tones after negative compared to neutral picture presentation. That was not the case here- neither group showed a difference in the response times to the oddball tones following negative picture presentation. The processing negativity and behavioral differences between the HIV group and our previous findings might be due to differences in experience and socioeconomic status (SES) between these two groups. Here, the HIV group reflects individuals of a disadvantaged background and low socioeconomic status (SES). Negative psychosocial factors encountered in the environment of persons with low SES possibly result in lower emotional reactivity since they encounter more frequent negative life events and chronic stressors (Stansfeld et al., 1998). It is also possible that the age difference between the HIV group here (Mage = 37.1 years, SD = 6.72) and the student group (Mage = 24.5, SD = 10.6) can account for the differences in the priming effect of the LPP (DeBoer et al., 2005). 4.4. Neuropsychological measures Overall, the HIV+ group exhibited many of the cognitive signs described in HIV-associated neurocognitive disorder (HAND) (Antinori et al., 2007; Reger et al., 2002). The HIV+ group scored significantly lower than the control group in tasks involving fine-motor control (Finger Tapping and Grooved Pegboard), language functioning (semantic verbal fluency and Boston Naming Task), processing speed (Trails-A) as well as self-report on the Beck Depression Inventory (see Table 1). Cognitive dysfunction in both asymptomatic and symptomatic HIV persons is known to be associated with abnormal fronto-striatal functioning as demonstrated by functional neuroimaging (Melrose et al., 2008). Furthermore, Diffusion Tensor Imaging (DTI) has established that myelin sheath damage may readily reduce cortical and subcortical white matter volume in HIV+ persons (Filippi et al., 2001; Ragin et al., 2005). Our findings of poorer fine-motor control and verbal functioning are also substantiated by reports of gray matter alterations in subcortical and cortical regions. Atrophy of the caudate nucleus, for instance, has been associated with reduced fine motor dexterity,

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psychomotor speed, verbal fluency and auditory attention (Kieburtz et al., 1996). The insula may also be another likely source of disruption to tasks involving pace and oculomotor control (Anderson et al., 1994; Fink et al., 1997). A recent structural MRI study comparing volumetric changes in HIV+ persons with varying viral load report marked decreases in insula volume along with an inverse relationship between the rate of insula thinning and Grooved PegBoard task performance (Kallianpur et al., 2012). Several others have reported thinning within the bilateral insula of HIV+ persons (Becker et al., 2012; Kassubek et al., 2001; Pfefferbaum et al., 2012). 4.5. Limitations The small sample size used in this study was a limitation in that we were not able to compare ERP measures as a function of disease progression (i.e., asymptomatic, symptomatic, and AIDS diagnoses); all subcategories of HIV infection were assimilated into a single clinical group. However, the findings that the HIV+ group, as a whole, show neurophysiological markers of blunted affect lays the groundwork for future studies to investigate affective changes with disease progression. Another limitation of this study was the inability to control for individual differences in affective processing style. ERP measures of emotion processing are shown to play a role in individual differences in affective style and automatic emotion regulation (Hajcak and Nieuwenhuis, 2006; Krompinger et al., 2008). It is possible that an avoidant coping style, common to ethnic-minority women living with HIV/AIDS (McIntosh and Rosselli, 2012), may have altered the emotion-appraisal process in one or both groups. Indeed, an avoidant coping style potentially explains the finding of an enhanced N1 in the HIV+ group after neutral and not negative pictures. We are currently carrying out a follow up study to address this concern. The reduction in the LPP amplitude in the HIV+ women may also be related to underlying changes in the EEG. In particular, the resting-state EEG shows distortions in alpha and delta frequencies in HIV+ individuals (Babiloni et al., 2012) and task-locked slow wave P3 ERP components are functionally related to EEG band frequencies in an oddball task (Ishii et al., 2009). Although excessive alpha activity can also influence late slow wave ERPs (Basßar et al., 2001), we attempted to avoid fatigue effects during ERP recording by including seven breaks throughout the ERP testing. Accordingly, we did not have any participants who showed excessive alpha activity locked to stimulus presentation. 4.6. General conclusion We tested the extent to which emotional visual stimuli can prime attention for subsequent auditory stimuli in HIV+, compared to ageand SES-matched HIV women. These results are of interest since HIV+ women face a number of psychological, physical, emotional, and health-related stressors each day. Moreover, stress associated with HIV infections are of higher incidence in ethnic minority women with low socioeconomic status (SES) (Rabkin et al., 2009). This study is the first to provide physiological evidence that the LPP, a measure of attention to emotionally-charged visual stimuli, is reduced in HIV infected individuals. We further show that the LPP reduction is related to a loss of affective priming to a subsequent auditory tone. Findings from this study set the stage for future imaging studies aimed at localizing differences in brain activation during emotional picture viewing in HIV+ compared to HIV individuals. It will be important to test to see if these findings are also present in HIV+ males. Although the LPP is produced in both males and females, females have been shown to produce LPP’s of greater amplitude compared to males when the pictures are highly arousing and have a negative valence (Gasbarri et al., 2006). An additional area of interest for future investigations will be to

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