The human immunodeficiency virus (HIV) crosses the blood-brain barrier and affects the brain early in the course of the disease (Avison et al., 2004; Gray et al., 1996; Power et al., 1993), causing neurochemical changes that alter functioning in selective populations of neurons (Kaul, Garden, & Lipton, 2001; Mattson, Haughey, & Nath, 2005).The neuropsychological and neuroimaging literature suggests that frontostriatal pathology is especially prominent in HIV (Chang et al., 2004; Chang et al., 2001; Ernst, Chang, Jovicich, Ames, & Arnold, 2002; Heaton et al., 1995; (Paul, Cohen, & Stern, 2003; Paul et al., 2007). The basal ganglia, in particular, are subject to pathology early in the course of the infection (Berger & Nath, 1997). There is evidence that blood-brain barrier disruption, resulting from direct infection or apoptotic changes in endothelial cells, may increase the viral burden in this region and allow entry of substances that are damaging for basal ganglia (Berger et al., 2000). HIV infection is also associated with tissue loss in frontal and parietal areas (Thompson et al., 2005). Neuroimaging studies of cognitive activation in HIV positive (HIV+) individuals have found increased activation in frontal and parietal cortical regions that are adjacent to those activated by the HIV negative (HIV−) control group (Chang et al., 2004; Chang et al., 2001; Ernst, Chang, Jovicich, Ames, & Arnold, 2002), that were interpreted in the context of compensatory activation induced by dysfunction of frontostriatal circuits in HIV+ individuals.
Recent neuroimaging studies have reported increased signal change in a cognitively intact HIV+ group compared to the HIV− group in lateral frontal and posterior parietal areas (Castelo, Sherman, Courtney, Melrose, & Stern, 2006). These findings also support the idea that HIV-related brain changes extend beyond the frontostriatal circuits to their parietal projections. Neuropsychological studies of cognition in HIV have shown that asymptomatic HIV+ individuals exhibit cognitive deficits consistent with dysfunction of frontostriatal circuits (Bogdanova, Diaz-Santos, & Cronin-Golomb, 2007; Bornstein et al., 1993; Castelo, Courtney, Melrose, & Stern, 2007; Heaton et al., 1995) and parietal cortical areas (Bogdanova & Cronin-Golomb, 2005; Olesen, Schendan, Amick, & Cronin-Golomb, 2007).
Neuropsychological measures of number processing, according to neuroimaging studies, have been linked to bilateral fronto-parietal cortico-subcortical circuits (reviewed in Dehaene, Piazza, Pinel, & Cohen, 2003; Hubbard, Piazza, Pinel, & Dehaene, 2005), including parietal areas that are important for visuospatial processing (Dehaene, Spelke, Pinel, Stanescu, & Tsivkin, 1999). Deficits in number processing and spatial function arise from changes in the cortico-striato-thalamic circuit that includes the basal ganglia, which are subject to pathology early in the course of HIV, and their cortical projection areas, the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal lobes. There has been a recent surge of interest in number processing studies in healthy adults (Gobel, Calabria, Farne, & Rossetti, 2006; Izard & Dehaene; Longo & Lourenco, 2007) and neglect patients (Cappelletti, Freeman, & Cipolotti, 2007; Doricchi, Guariglia, Gasparini, & Tomaiuolo, 2005; Priftis, Zorzi, Meneghello, Marenzi, & Umilta, 2006; Rossetti et al., 2004; Zorzi, Priftis, Meneghello, Marenzi, & Umilta, 2006), significantly extending our understanding of numerical cognition, in particular mental number line and spatial representation of a number. To our knowledge, there are no published studies assessing numerical cognition in HIV.
In the present study we used a series of neuropsychological measures to investigate numerical and visuospatial processing in the early asymptomatic stage of HIV. This study examined the relation between numerical distance estimation and spatial orientation in asymptomatic HIV+ individuals.
Mental Number Line
Galton (1880) first introduced the concept of the spatial representation of numbers similar to a mental number line. Since then, there have been many behavioral, neuroimaging and lesion studies investigating the mechanisms underlying numerical processing and the abstract concept of a mental number line.
Luria (1945, 1962) demonstrated that lesions to the parietal area lead to number processing deficits based on a disorder of spatial synthesis, or a disturbance of the category of direction of space. When parietal systems of the brain are damaged, the spatial reference system, essential for calculation, is lost. Impairment of the spatial coordinate system with respect to numbers is manifested in the deterioration of a number’s decimal structure. With respect to calculation, the impairment of the spatial coordinate system is demonstrated by spatial errors on a mental number line. According to Luria’s model, we can expect that parietal lesions would lead to the impairment of the concept of number as well as a specific spatial impairment in number processing.
Restle (1970) suggested that the representation of numbers could be spatially organized along a mental number line, a concept that recently has been expanded and popularized by Dehaene. Dehaene’s triple-code model (Dehaene, 1992; Dehaene & Cohen, 1997) postulates that a magnitude code is subserved by the parietal lobes, and that numbers are represented as a distribution of activation on an oriented number line. Recent reports suggest that number magnitudes are represented spatially along a continuous analogue mental line, with smaller numbers located to the left and larger numbers to the right of the line (reviewed in Hubbard et al., 2005).
The left-to-right orientation of the mental number line is currently a subject of investigation in the numerical cognition literature. Dehaene, Bossini, and Giraux (1993), and Dehaene, Dupoux, and Mehler (1990) demonstrated the SNARC effect (Spatial Numerical Association of Response Codes), the observation that individuals respond to smaller numbers faster with their left hand, and to larger numbers faster with their right hand. This phenomenon was observed even on a task that did not require processing the magnitude of the number stimuli, such as indicating whether the number was even or odd. The SNARC effect provides further evidence for the spatial nature of mental number representation and suggests left-to-right number organization on a horizontally oriented mental number line.
Neural Mechanisms for Mental Number Line
While exact neural mechanisms involved in number line processing remain unknown, some studies suggest that mental number line orientation relies mostly on parietal areas (Hubbard et al., 2005), whereas others suggest that mental number line orientation relies on spatial working memory mechanisms involving frontal areas (Doricchi et al., 2005). Several studies indicate that numerical quantity judgments, used in mental number bisection tasks, involve activation of the intraparietal sulcus (horizontal segment) bilaterally, the left precentral gyrus, and prefrontal areas (Dehaene, Molko, Cohen, & Wilson, 2004; Dehaene et al., 2003; Walsh, 2003). Repetitive transcranial magnetic stimulation (rTMS) studies provide further insight into the mechanisms of mental number line processing. Gobel and colleagues (2006) used rTMS over parietal and occipital areas in healthy individuals during a mental number bisection task. Performance during control trials was similar to performance reported in physical line bisection where participants underestimated the midpoint of the numerical interval (that is, exhibited leftward bias). rTMS over the right posterior parietal cortex produced a significant rightward shift of the perceived midpoint of the numerical interval, simulating ‘spatial’ neglect in healthy subjects. rTMS over the occipital cortex did not produce any effect on bisection performance. The study provided further evidence for spatial representation of a mental number line and for the involvement of the right posterior parietal cortex in the spatial representation of numbers.
Physical Line Orientation
Right posterior parietal cortex has been implicated in physical line bisection, a task frequently used in numerical cognition studies. Neuroimaging (Fink et al., 2000) and patient (Doricchi & Angelelli, 1999) studies showed that physical line bisection is associated with processing by the inferior and superior parietal lobes. Additionally, a neuroimaging (fMRI) study of physical line bisection judgment (Landmark task) indicated that processing horizontal and vertical physical lines activates anatomical networks in the right inferior parietal cortex (Fink, Marshall, Weiss, & Zilles, 2001). The study reported no significant interaction between the physical line bisection judgment task and stimulus orientation, suggesting that the activation of inferior parietal cortex during the Landmark task reflects visuospatial judgment irrespective of line orientation.
Relation between Spatial and Numerical Cognition
The studies of the SNARC effect provided evidence for spatial-numerical interactions (reviewed in Hubbard et al., 2005) Moreover, Caessens, Hommel, Reynvoet, and van der Goten (2004) demonstrated that the SNARC effect or spatial-numerical interaction occurs regardless of input or output modality. This study measured the spatial-numerical interaction without using visual digit presentation. Participants were presented with visual stimuli (arrows, then colors) and were asked to respond verbally with ‘one’ or ‘two.’ The automatic activation of numerical information interfered with participants’ responses to the orientation of an arrow.
Lesion studies provide additional evidence for the close relation between spatial and numerical domains (Benton, 1992; Mayer et al., 1999; Roux, Boetto, Sacko, Chollet, & Tremoulet, 2003). The classic case of Gerstmann’s syndrome (Gerstmann, 1940) showed that the combination of number processing and spatial deficits are frequently observed in patients with lesions of the parietal lobes, specifically in the left angular gyrus. Disorders such as acalculia, agraphia, finger agnosia and right-left confusion typically associated with left angular lesions share close anatomical and possibly functional neural networks (Roux et al., 2003)
Studies of patients with left hemispatial neglect provide further insight into our understanding of spatial and numerical cognition. Neglect patients typically bisect horizontal lines to the right of the veridical center, showing rightward bias, whereas healthy individuals exhibit systematic leftward bias, or pseudoneglect, on a physical line bisection task (Bowers & Heilman, 1980). Recent studies of neglect that used the mental number line bisection task in horizontal orientation also showed that neglect patients exhibit rightward bias on bisection, whereas healthy participants demonstrate leftward bias. Zorzi, Priftis, and Umiltà (2002) found that neglect patients produce errors on a mental number line bisection task, similar to the errors usually observed on a physical line bisection task (see also Priftis et al., 2006; Zorzi et al., 2006). Longo and Lourenco (2007) reported leftward bias (pseudoneglect) in both mental number line and physical line bisection in young healthy participants, and found that the magnitude of pseudoneglect in these tasks correlated across participants. The investigators concluded that hemispheric asymmetries in spatial attention apply to both physical and mental numerical space.
The imbalance of attention distribution produces ipsilesional (rightward) bias in neglect patients, whereas healthy participants may exhibit a “culture-induced” leftward orienting on tasks that require reading, writing and numerical processing. In our culture we orient to the left when we are about to start reading, writing a word or writing down a multi-digit numeral, as our writing and our attentional scanning habits are organized in the left-to-right direction (Fias & Fischer, 2005; Opfer & Thompson, 2006). We can hypothesize that on a task that requires estimation of numerical distance (for instance, place “7” on a horizontally presented visual [physical] number line from “0” to “10”), we orient to the left first in an attempt to “measure” the distance from the starting point of “0” to the required “7.” It seems equally plausible that our attention is directed towards the left when we estimate the numerical distance on a mental number line, similar to the visual number line. The evidence for this is derived from the SNARC studies. The SNARC studies also demonstrated that American children do not show a SNARC effect until age nine (Berch, Foley, Hill, & Ryan, 1999), which is determined by their educational experience. Additionally, the SNARC studies showed a reversed effect in adult [Iranian] individuals whose first language was Arabic, and who write from right-to-left (Dehaene et al., 1993; reviewed in Hubbard et al., 2005)
Priftis et al. (2006) reported dissociations between implicit and explicit processing of the mental number line in neglect patients. Here, patients with left neglect (right hemisphere damage) performed a mental number bisection task and a modified version of the SNARC task. Results revealed a neglect effect on the mental number bisection task only. The investigators linked the impaired performance in mental number bisection to an attention-orienting bias during active exploration or manipulation of the number line.
The neglect literature has also established a dissociation between visual numerical and non-numerical representations of space (reviewed in Bisiach & Vallar, 2000; Rossetti et al., 2004; Zorzi et al., 2006). Zorzi et al. (2006) investigated the spatial representation of numerical and non-numerical sequences in neglect patients. Patients were asked to complete the bisection of visual lines and the mental bisection of number intervals, letter intervals, and month intervals. There was a rightward bias on visual line and similarly on mental number interval bisection, but no effect on non-numerical sequences. The investigators concluded that the spatial layout for numerical representations on a mental line is number specific and does not apply to all ordered sequences. The study confirmed their earlier isomorphism hypothesis (Zorzi et al., 2002), which postulated that the mental number line organization strongly resembles the structure of a physical line.
A recent study of neglect patients (Cappelletti et al., 2007) examined the orientation of mental number lines and physical line bisection. In this study, all five patients with neglect exhibited a rightward bias for physical and horizontally oriented mental number lines. Three of the patients also demonstrated an upward bias for vertically oriented mental number lines, while two showed no bias. The investigators concluded that horizontal and vertical neglect can associate or dissociate in neglect patients, suggesting partially independent mechanisms for processing horizontal and vertical mental number lines.
Though neglect has been most often described in the horizontal dimension, it can be manifested in all three dimensions: horizontal (lateral), radial (near-far), and vertical (altitudinal) (Kageyama, Imagase, Okubo, & Takayama, 1994; Kori & Geldmacher, 1999; Vallar, Guariglia, Magnotti, & Pizzamiglio, 1995). Moreover, the processing of horizontal and vertical physical lines activates the same anatomical networks in the right inferior parietal cortex (Fink et al., 2001).
Physical Number Line
Our preliminary study of asymptomatic HIV+ and healthy matched individuals examined physical number line orientation (a pencil-and-paper task to assess visual number line orientation) in two dimensions, horizontal and vertical, and found that each group exhibited a similar bias on vertical and horizontal physical number line orientation (Bogdanova & Cronin-Golomb, 2005). Taken together, the findings from the studies of healthy and neurologically impaired adults, which showed the same directional bias for the mental number line and physical line bisection, lead us to hypothesize that (a) the physical number line will have numerical and spatial properties that are similar to those of the mental number line. Additionally, the studies of the SNARC effect that demonstrated similar spatial-numerical interactions regardless of input and output modality, and neglect studies allowed us to hypothesize that (b) the internal mental number line activated during these tasks can be applied (mentally rotated) in more than one dimension, and that (c) the physical number line will have similar numerical properties and spatial integrity in both horizontal and vertical orientations. Although no studies have investigated the neural basis of physical number line orientation, findings from previous studies allow us to hypothesize that (d) active direct exploration and manipulation of both physical and mental number lines will involve the same attentional orienting bias. We hypothesized that (e) operation within the physical number line may rely on neural networks involved in both physical line and abstract numerical (mental number line) orientation. Based on the previous studies that established a dissociation between visual numerical and non-numerical representations of space, and our own preliminary results, we predicted (f) a dissociation between the processing components of numerical distance (physical number line) and physical space (physical line bisection) in our HIV+ group, as we hypothesized that there is a differentiation between the neural networks involved in these processes. The neural areas implicated in mental number line processing, frontostriatal and parietal, present particular interest to our study of asymptomatic HIV+ individuals, as we attempt to explore the impact of HIV infection on the brain beyond well-studied frontostriatal circuits, specifically to include parietal-based spatial functions.
We had two main aims of the present study. The first was to investigate the effect of HIV infection on cognitive function, in particular, the relation of numerical and spatial cognition in individuals with HIV in its early asymptomatic stage. Because frontostriatal circuitry is affected in HIV, and this circuitry includes projections to the parietal lobes, the expectation is that parietal-based numerical processing and visuospatial function should be impaired as a consequence of HIV. The second aim was to explore the underlying mechanisms for both physical and mental number orientation using several modes of presentation and response: mental number line bisection (verbal input and verbal output), physical number line orientation on visually-presented number lines (visual and verbal input, visuo-motor output), and physical line bisection (visual input, visuo-motor output). To further investigate the nature of the relation between numerical and spatial processing, the physical number line was presented in both horizontal and vertical orientation.