The effects of HIV on the brain remain a concern even in the era of combination antiretroviral therapy (CART) as around 50% of infected individuals are estimated to suffer from some degree of cognitive impairment . Currently, the effects of HIV on the brain are assessed by neurocognitive testing and are termed HIV-associated neurocognitive disorders (HAND) . With the advent of CART, there has been some success in the treatment of HAND, as the more severe forms of these disorders have decreased in incidence [3,4]. However, with the resultant decrease in mortality there has been an increase in the overall prevalence of HAND [3–5]. Three categories of HAND based on neuropsychological assessment are currently recognized, namely HIV-1-associated asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-1-associated dementia (HAD), which is the more severe form of the disorder .
It must be noted, however, that there is some debate regarding the ANI category. The absence of clinically detectable loss of function raises the issue of whether the category is clinically valid at all. The presence of mild neuropsychological impairments may be accounted for by premorbid conditions, other HIV-related comorbidities as well as normal ageing . As a group, the milder forms of cognitive impairment (i.e. MND and ANI) are highly prevalent and may have a substantial impact on health-related outcomes and quality of life. There is some evidence that the presence of MND, and possibly ANI, could represent early, potentially reversible functional and pathological changes . The problem of establishing mild-to-moderate loss of function in developing world settings is a particular challenge. Reasons include individuals frequently under-reporting self-rated impairment . This makes clinical diagnosis difficult, and the need for reliable biomarkers an even more pressing concern [6,9].
Furthermore, because of a lack of biomarkers sensitive to early changes during HAND, little is known of the underlying neuropathological events leading up to impairment seen in HAND [9,10] which could potentially aid early diagnosis and treatment strategies.
To understand how the effects of HIV on the brain develop into HAND, it is necessary to know which brain structures are primarily involved, and how this relates to viral infection. The typical neuropsychiatric disorder associated with untreated HIV is best described as a ‘sub-cortical’ or ‘fronto-sub-cortical’ dementia , and this is supported by neuropathological findings, with the features of HIV-encephalitis (HIVE) being most commonly found in the putamen and caudate [12–14]. HIV is thought to disrupt the dopamine-rich striatum by means of neuroinflammation stimulated either by viral proteins such as Tat and gp120 [15,16] or by activated microglia .
One potential method of investigating the underlying neuropathological mechanisms leading to HAND is blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) . This technique includes task-based fMRI, resting state fMRI , arterial spin labelling (ASL)  as well as contrast-aided ‘perfusion’ fMRI intended to measure regional cerebral blood flow (rCBF)  and cerebral blood volume (CBV) . There is a growing literature investigating the effects of HIV on brain function utilizing these fMRI techniques. fMRI is potentially a sensitive and safe technique to detect functional deficits, even in the absence of overt neurocognitive impairment in HIV . These functional changes could represent the earliest measurable effects of the virus on human brain function, thereby providing a clear signal of involvement even before neuropsychological deficits are apparent. Showing suitable spatial and temporal resolution, as well as being related to specific functional processes, fMRI has the potential to explore these functional changes associated with HIV infection and to elucidate how these relate to disease severity .
Although several reviews of neuroimaging in HIV have been conducted [24–27], to our knowledge no meta-analysis has been performed specifically for fMRI studies, and particularly none have utilized recently developed quantitative methods for meta-analysis in neuroimaging . The need for such a review is underscored by a previous review highlighting the potential of functional and structural neuroimaging techniques in HIV in early detection and treatment monitoring .
The present study aims to systematically review the literature reporting fMRI findings in HIV-infected patients and to quantitatively investigate the effects of HIV by means of an activation likelihood estimation (ALE)  on brain function, and to relate these effects qualitatively to measures of cognitive impairment (i.e. HAND), mechanisms of HIV pathogenicity, treatment effects as well as the effect of HIV on functional haemodynamic vascular coupling.
The qualitative systematic search method we used was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) . A literature search was performed in October 2012 using two online search engines, the National Library of Medicine (PubMed) and Sciverse Scopus. The following search terms were used: fMRI, BOLD imaging, blood oxygen level dependent, fMRI, arterial spin labeling, resting state, resting state fMRI, functional connectivity, resting-state fMRI, HIV dementia, HIV-associated neurocognitive disorder, HIV-associated neurocognitive disorder, HIV brain injury, HIV brain injury, HIV cognitive impairment, HIV cognitive impairment, HIV brain function, HIV brain function, HIV brain activation, HIV brain function, abnormal brain activation, abnormal brain function. References of the identified studies were cross-checked for any additional relevant studies.
All identified articles were captured in a standard electronic database. General study information (author names, publication dates, etc.), patient population demographics, clinical assessment instruments and diagnostic criteria used, all available neuropsychological test results, potential confounds as well as fMRI findings were captured (See Table 1 for summary).
Eligibility criteria for qualitative systematic review
BOLD fMRI studies in HIV+ CART treated/treatment-naive human adult (male/female) patients were included in the present review. As our primary aim was to investigate brain dysfunction associated with HIV infection, we did not limit our review to patients with documented HAND. Both prospective and longitudinal studies were included and no time frame was specified.
Only original studies with at least one HIV+ group were included. Duplicates were identified and removed. Studies that included a cohort that was previously reported were noted and not considered in the meta-analysis. Studies in all languages were considered.
Meta-analysis eligibility criteria
Although all variants of BOLD fMRI imaging where included in the systematic review, studies specifically examining HIV-related brain dysfunction using MRI imaging methods that would provide suitable peak activation co-ordinates as well as comparable fMRI paradigms were considered for inclusion in our ALE meta-analysis.
The subset of studies that provided local maximum activation co-ordinates of inter-group differences of a HIV+ group and a control group were grouped together according to the functional paradigms that were used. Where two or less studies that utilized similar fMRI paradigms were available, those paradigms were excluded, as we considered this too few to provide useful information in an ALE meta-analysis. Also, we only included studies that utilized paradigms examining higher cognitive functions. To be included, studies needed to address potential confounding chronic medical or neuropsychiatric illnesses as well as substance abuse. Studies that could not account for the effects of advanced age (> 65 years) were also excluded from the meta-analysis.
For assessing cross study agreement, a meta-analysis was performed using GingerALE version 2.1 (www.brainmap.org)  on selected studies. In brief, this method estimates the above-chance convergence of activation by testing the likelihood of a uniform spread throughout the brain. The GingerALE method seeks to delineate where the inter-experiment convergences are higher than would be expected if the results were independently distributed . Peak activational co-ordinates are used to derive three-dimensional Gaussian probability distributions of the regional activation variability of a given co-ordinate. In the current meta-analysis, wherein activation differences between HIV+ and HIV− groups are investigated for each of the experiments, a patient number of the smaller group was used to provide the full-width-half-maximum (FWHM) value, giving a more conservative estimate. The resulting modelled activation probabilities are combined into a modelled activation map. ALE scores are then computed for each voxel based on the union of the modelled activation maps. It is assumed that functional activation occurs mainly in grey matter. The resulting ALE computation is therefore restricted to a broadly defined grey matter mask, based on a more than 10% chance of a voxel to be grey matter as defined in the International Consortium for Brain Mapping (ICBM) tissue probability maps [30,32]. This resulting ALE map is then tested against an empirically derived null-distribution. This random-effects inference is therefore based on the above-chance convergence between experiments, not between foci. Results were corrected for multiple comparisons using the false discovery rate (FDR) as is standard in GingerALE. Results are reported at a 0.05 FDR rate. The peak co-ordinates of comparable BOLD fMRI group differences between HIV and healthy controls were used, and if needed, converted into Talaraich space using the GingerALE conversion tool. We report the results of the meta-analysis first, followed by the complementary pertinent information gathered from the remainder of the studies included in the qualitative systematic review.
In total, 42 matching articles were retrieved on PubMed and 236 on Scopus, from which 21 studies were found to satisfy eligibility criteria for this review, totalling 468 HIV+ participants and 270 controls. We included 19 cross-sectional studies [21–23,33–48], one longitudinal study  and one study reporting a posthoc analysis of an already included study . Of the 21 studies included in the review, a subset of six BOLD fMRI studies utilizing similar fronto–parieto–striatal engaging tasks were included in the ALE meta-analysis [23,34,37,40,48,49]. These six studies included peak activation differences of 207 participants (105 HIV positive, 102 controls). Of the six studies included, all controlled for confounds. Five studies excluded participants with a past history of substance dependence [34,37,40,49], whereas one study excluded participants with recent substance abuse . Four studies confirmed no current substance use by means of urinary drug tests [23,34,49,51]. One study included a patient with a history of past substance abuse, in the absence of dependence . The study controlled for this by including a control matched for substance use. All six studies included patients below 65 years of age. Study information is summarized in Table 1.
The 21 fMRI studies included in the systematic review consisted of 468 participants (73% male, 27% female) with weighted mean age of 42 ± 4 years. Virtually all of the participants were from the United States (n = 20), where the clade B viral subtype is most prevalent , and one study included participants from China. The weighted mean CD4+ cell counts for all studies was 444.79 ± 137.43 cells/μl. The majority (82%) of HIV+ study participants were receiving CART.
Cognitive impairment measurements ranged from no impairment to HAD: Only three studies included patients with all categories of cognitive impairment. Seven studies included patients with mild/moderate impairments and three included all cognitive impairment categories. Six studies were performed in relatively cognitively unimpaired populations and five studies did not report on the degree of cognitive impairment present in the study participants.
Of the 21 studies included in the systematic review, six task-based BOLD fMRI studies reported activation of the fronto–parieto–striatal network in healthy controls [23,34,37,40,48,49]. We were therefore able to group all of these studies together, as they utilized similar information processing steps – that is, selective attention to visual information, retaining of relevant information in working memory and manipulation of this information to successfully perform the task [53,54].
The fMRI paradigms we identified as being suitable for our meta-analysis included a sequential working memory letter NBACK paradigm (n = 1) , nonverbal visual attention tasks (n = 3) [34,37,49], mental rotation (n = 1)  and a semantic event sequencing task (n = 1) .
Significant convergence of relative increases found in activation likelihood estimation analysis
Two significant clusters were found at the recommended cluster threshold of 112 mm3, based on the FDR threshold (P = 0.05), which calculates the number of potential false positives that could arise due to the multiple comparisons that were performed. The clusters were located on the left inferior frontal gyrus (IFG) and the left caudate. Although some increases were seen in the parietal cortices, these clusters were below the cluster threshold. The majority of convergence was therefore found in the fronto–striatal regions (Fig. 1; Table 2).
This article reports the results of the first quantitative meta-analysis of BOLD fMRI literature on the effects of HIV on brain function. Of the 21 studies included, six contained sufficient data for an ALE meta-analysis . Overall, the meta-analysis provides evidence to suggest that HIV infection causes hyperactivation in the IFG as well as left caudate, implicating the fronto–striatal system in HAND. Although individual studies report on findings in other regions including the insula, parietal cortex, thalamus, supplementary motor area, precentral gyrus and occipital cortex (see Table 1), the majority of the convergence measured across studies was confined to the fronto-striatal network involving the left IFG and the left caudate.
This is not surprising, considering that while tasks requiring simple attention are often preserved in HIV, except in cases of severe HAD, it is well recognised that tasks requiring complex information processing and selective attention are often sensitive to the effects of HIV .
Apart from task related activity, which actively engages the cortex, several fMRI BOLD studies report baseline rCBF reductions in the fronto–striatal system. Chang et al. reported bilateral reductions of rCBF in bilateral inferior frontal gyri and Ances et al. found reductions in the lentiform nuclei [21,35,41]. Furthermore, a relationship was found between reduced caudate rCBF and greater neurocognitive impairment .
Relationships between functional magnetic resonance imaging fronto–striatal findings and HIV-associated neurocognitive disorders
Comparisons across studies investigating how brain functional differences relate to cognitive impairment are complicated by the different methods of neurocognitive assessment utilized across studies. Despite the fact that the majority of studies included participants with mild or no measurable cognitive impairment, measurable functional brain changes were demonstrated in these patients. This suggests that fMRI has the potential to detect early effects in HIV-infected patients in the absence of overt cognitive impairment, and that it is sensitive to detecting underlying early neurobiological effects of the virus [23,36,40,41,43,49]. Future studies should address whether these functional brain changes are precursors to HAND, or whether they perhaps even represent physiological responses to HIV infection that protect against the development of HAND.
Mechanism of fronto–striatal impairment
The exact mechanism of the reported fronto–striatal activation changes in HAND remains unclear. It is generally considered that HIV-mediated cognitive impairment is the result of viral-induced neuro-inflammation, as the degree of monocyte activation as well as the level of microglial activation has proven to be a more reliable correlate with HIV-D than viral load or even active viral replication [56,57]. One possibility, proposed by Ernst et al. is that this HIV-induced inflammation impairs neural efficiency with resultant compensatory increases in neuronal activation with task demands. In support of their hypothesis they reported a positive correlation between BOLD signal strength in the lateral prefrontal cortex as well as the posterior parietal cortex, with elevated basal ganglia metabolites including myo-inositol and total creatine as measured with magnetic resonance spectroscopy that are putatively predominant in glial cells . In addition, dopamine neurocircuitry may be involved. It is well recognized that dopamine is an important modulator of the activity of the fronto–striatal networks , thereby making it a likely candidate for involvement in dysfunction in these systems. In support of this possibility is the finding that altered dopaminergic neurotransmission takes place as early as 2 months following immunodeficiency infection [17,59–62], and in both HIV-infected humans and SIV-infected macaques increased dopamine availability was observed [63,64], whereas intracellular levels of dopamine were reduced [17,59,65]. Further validation studies examining such neurochemical and immunological disturbances in conjunction with fMRI have yet to be performed.
Limitations of reviewed studies
The fMRI studies performed in HIV-positive patients thus far are limited by small sample sizes, ranging from 6 to 42 HIV-positive participants per study. Participants tend to be mostly male, therefore possible sex differences on fMRI activation are uncertain. The potential effect of HIV on functional haemodynamic vascular coupling (i.e. the basic assumption that changes in regional blood flow reflect neuronal activity) still needs to be fully explored, with studies to date reporting conflicting results [38,44]. More importantly, fMRI studies tend to include samples of patients mostly treated with CART. Two studies have specifically investigated the possible effects of CART, demonstrating potential CART-related signal increases in the frontal and parietal cortices [37,39]. More CART naive sample groups are therefore needed to explore the effects of HIV in the absence of CART.
As viral transmission is often associated with intravenous drug abuse, especially in the United States where up to 15–30% of intravenous drug abusers are HIV+ [6,66], care has to be taken to account for its effects. Specifically abuse of opiates and amphetamines has been associated with a more severe clinical course as well as a more rapid progression of HAND . As drugs of abuse have their own direct effects on the fronto–striatal system , as well as potential immune-modulatory effects , there is a need to explore their confounding as well as synergistic effects in more detail [69,70]. Two fMRI studies included in the current review examined potential synergistic effects between HIV and drugs of abuse: Meade et al. demonstrated HIV-positive patients who abuse cocaine have abnormal functioning in their executive networks relative to substance naive HIV-positive controls, when performing a delay-discounting task. Beau et al. furthermore showed both HIV and a previous history methamphetamine dependence have potentially independent effects on the lentiform nuclei function during a tapping task as well as cerebral blood flow. Although few in number, these studies underscore the necessity to control for the various forms of drug-related disorders. Importantly, most studies included in the current review controlled for past drug dependence (n = 12), with 11 studies performing urinary drug tests immediately prior to scanning.
The impact of other comorbidities such as opportunistic infections as well as head injuries need to be considered. Most studies in the current review excluded comorbid general medical conditions on history. However, only three studies performed serological tests for syphilis. The effects of hepatitis C as well as cardiovascular disease, considered potentially important comorbid conditions in HAND, have yet to be explored in conjunction with fMRI measurements [6,72,73].
This systematic review and meta-analysis shows convergence in findings of hyperactivation in the left IFG and left caudate in patients with mild-to-moderate HAND. This increased activation could potentially be due to compensation in the fronto–striatal–parietal network, and could be linked to abnormal striatal dopaminergic neurotransmission or perhaps due to HIV's general predilection for deep grey matter areas. Important confounding effects of HIV on functional haemodynamic vascular coupling, CART, drugs of abuse, co-infections such as neurosyphilis and hepatitis C as well as cardiovascular disease in an ageing HIV population need to be explored.
S.D.P. conceived the study, reviewed articles, performed meta-analysis and participated in the writing of the article. M.V. aided study conception, assisted in analysis, interpretation and participated in article writing. J.A.J. assisted in review of articles as well as providing feedback on the approach, interpretation and review of article drafts. E.K. aided interpretation of the findings as well as aiding in writing of the article. D.J.S. and R.E. provided feedback on study approach, interpretation of data as well as article review. The authors would also like to thank Dr Laila Asmal, Dr Karen Cloete and Dr Sanja Kilian from Stellenbosch University for their valuable support in preparation of the manuscript.
S.D.P. is supported by an NRF international research-training grant (NRF 1533) as well as a research career award from the Biological Psychiatry Special Interest Group of the South African Society of Psychiatrists. J.A.J. is currently receiving grants from the NIMH and receives payment for lectures by Sanofi. D.J.S. serves on the board of Eli-Lily and Lundbeck, and receives consultancy fees from Novartis, Servier and Biocodex. He also receives payment for lectures from Eli-Lily, GlaxoSmithKline, Lundbeck and Servier. R.E. is supported by a grant from the Stanley Medical Research Institute, as well as payment for lectures by Janssen, Servier and Lundbeck.
Conflicts of interest
The authors declare no conflicts of interest.
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