Research report
Compromised fronto-striatal functioning in HIV: An fMRI investigation of semantic event sequencing

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Abstract

The human immunodeficiency virus (HIV) damages fronto-striatal regions, and is associated with deficits in executive functioning. We recently developed a semantic event sequencing task based on the Picture Arrangement subtest of the Wechsler Adult Intelligence Scale-III for use with functional magnetic resonance imaging (fMRI) and found recruitment of dorsolateral prefrontal cortex and basal ganglia in healthy participants. To assess the impact of HIV on the functioning of the basal ganglia and prefrontal cortex, we administered this task to 11 HIV+ and 11 Control participants matched for age and education. Neuropsychological evaluation demonstrated that the HIV+ group had mild impairment in memory retrieval and motor functioning, but was not demented. Morphometric measurements suggested no atrophy in basal ganglia regions. The results of the fMRI analysis revealed hypoactivation of the left caudate, left dorsolateral prefrontal cortex, and bilateral ventral prefrontal cortex in the HIV+ group. Functional connectivity analysis demonstrated less functional connectivity between the caudate and prefrontal cortex and basal ganglia regions in the HIV+ group. In contrast, the HIV+ group demonstrated increased activation of right postcentral/supramarginal gyrus, and greater connectivity between the caudate and this same anterior parietal region. The results of this study extend previous investigations by demonstrating compromised function of the caudate and connected prefrontal regions in HIV during cognition. This disruption of fronto-striatal circuitry likely precedes the development of cognitive impairment in HIV.

Introduction

The human immunodeficiency virus (HIV) is known to affect cognition, and the most pronounced declines from early to late stage HIV infection include changes in motor functioning, information processing speed, and executive functioning [39]. Within the domain of executive functioning, researchers have identified impairments in inhibition [18], [24], set shifting [41], manipulation within working memory [26], [41], and planning and cognitive sequencing [41], consistent with the hypothesis that changes in fronto-striatal circuitry may mediate HIV-associated cognitive decline. Structurally, neuroradiological studies have found that smaller caudate volume is associated with HIV disease [3], [4], [20], [45], and smaller caudate volume correlates with poorer performance on cognitive tests in patients with advanced HIV disease [21]. Volume loss in the medial frontal and premotor cortices is found in patients with AIDS, and thinning of the prefrontal cortex (PFC) in particular is associated with the severity of cognitive impairment in patients with AIDS [47]. Finally, functional MRI (fMRI) studies have found functional changes in PFC regions during tasks of attention and working memory [47], [9], [10], [14]. Together these studies provide evidence that HIV is associated with executive dysfunction, and with changes in fronto-striatal regions.

Although previous fMRI tasks used with HIV subjects have demonstrated impaired functioning in PFC [47], [9], [10], [14], and medial temporal systems [8], to date tasks that are known to activate the basal ganglia (BG) have not been used with this patient group. The purpose of the present study was to investigate the integrity of fronto-striatal circuitry in HIV during executive functioning, specifically by administering a semantic event sequencing task that is known to recruit both PFC and BG regions [48], [49]. The semantic event sequencing task administered in this study is an adaptation of the Picture Arrangement subtest of the WAIS-III [51]. This fMRI task requires subjects to plan ahead and sequence meaningful events chronologically, and reliably recruits PFC-BG circuits in healthy subjects [48]. This task has also been used to demonstrate changes in fronto-striatal functioning in patients with Parkinson's disease [49]. In the current study, between-group contrasts and functional connectivity analyses enabled us to examine how HIV affects BG-PFC regions. We hypothesized that the HIV group would demonstrate differential signal change in both the BG and PFC, and reduced functional connectivity between the BG and PFC, supporting the theory that compromise to fronto-striatal circuitry underlies cognitive deficits in HIV.

Section snippets

Participants

Eleven HIV+ (age = 40.8, S.D. 7.1, range: 29–52 years) and 11 HIV− (age = 40.9, S.D. 8.7, range: 27–54 years) male Control volunteers participated in this study. Groups were matched for education (HIV+; years = 16.3, S.D. 1.5. range: 14–18 years.; Control 16.9, 1.8, range: 13–19 years; t = .9). Subjects were recruited via advertisements in local newspapers and flyers posted at community health centers. Subjects were excluded if they had a history of neurological illness, head injury, psychiatric

Neuropsychological battery

All results from the neuropsychological battery are reported in Table 1. When corrected for multiple comparisons, the only difference between groups was on the BDI-II, indicating that the HIV+ group reported more symptoms of depression. When we did not correct for multiple comparisons, the HIV+ group had poorer performance on the CVLT Delayed Recall (t = −2.1, p < .05), the Grooved Pegboard non-dominant hand number of drops (t = 2.4, p < .05), and Finger Tapping test (FTT) non-dominant hand (t = −2.7, p < 

Discussion

The purpose of our investigation was to examine the integrity of fronto-striatal circuitry underlying executive functioning in HIV. Our HIV+ and Control groups were matched for age and education, and results of the cognitive testing revealed only mild cognitive compromise, with subtle declines in long-term memory retrieval and motor functioning in the HIV+ group. There were no behavioral differences between groups on the fMRI task. Results of the structural MRI analysis found no evidence for

Conclusions

In summary, we conclude that fronto-striatal functioning is compromised in patients with HIV. Our semantic event sequencing task is dependent on interactions between the prefrontal cortex and the basal ganglia [48], and this result adds to a growing body of literature suggesting that impairments to the fronto-striatal system underlie cognitive deficits in HIV. The HIV+ group exhibited this altered pattern of functional activity in the context of preserved behavioral performance, mild cognitive

Acknowledgements

We thank Andrew J. Worth for assistance with the analysis of the structural MRI data. We thank Renee M. Poulin for assistance with fMRI data analysis, Yakeel Quiroz-Gaviria for assistance with the neuropsychological data analysis, and Alexandra Oleinik for assistance with manuscript preparation. We are grateful to our participants for their time and dedication. Supported by NIH ROI NS40239, NINDS F31 NS052126, and F31 NS054570. We acknowledge support from the Athinoula A. Martinos Center for

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