Abstract

Converging evidence from neuropsychological and neuroimaging studies suggests that the ability to maintain an alert, ready-to-respond state is mediated by a network of right-hemisphere frontal and parietal cortical areas. This right lateralization may help to explain why visuospatial hemineglect, a cluster of deficits in detecting and responding to contralesional stimuli, is more common and persistent after right-hemisphere lesions. Indeed, it has been hypothesized that this asymmetry reflects a direct, functional link between alertness and spatial attention. In the present study, we investigated whether a pharmacologically induced increase in alertness would influence lateral bias in healthy people. Eighteen healthy participants were each given placebo or the psychostimulant drugs methylphenidate 40 mg or modafinil 400 mg on separate days and completed an hour-long version of the spatially sensitive landmark task. For those participants who demonstrated the expected alerting effect of modafinil, there was a significant Condition by Time interaction, consistent with the effects of the drug resisting time-on-task rightward drifts in spatial bias in the placebo condition. In contrast, no effect of methylphenidate on spatial bias was observed. These results suggest that spatial bias may be modulated by a psychostimulant-induced increase in alertness, supporting the hypothesis of a direct, functional link between right-hemisphere systems controlling alertness and visuospatial attention.

INTRODUCTION

Nonspatial deficits are increasingly seen as cardinal symptoms of visuospatial hemineglect. Patients with neglect have been shown to perform poorly on a range of tasks requiring nonspatial attentional functions, including rapid serial visual presentation (RSVP) (Shapiro, Hillstrom, & Husain, 2002; Husain, Shapiro, Martin, & Kennard, 1997) and sustained attention tasks (Robertson et al., 1997; Hjaltason, Tegner, Tham, Levander, & Ericson, 1996). Furthermore, patients with right-hemisphere (RH) lesions who perform poorly on sustained attention tasks tend to show a greater deficit in awareness for left-sided stimuli (Robertson et al., 1997), suggesting that a deficit in sustained attention may contribute to the severity of spatial inattention.

In support of this hypothesis, Robertson, Mattingley, Rorden, and Driver (1998) found that modulations of alertness could affect spatial bias within individual patients with RH lesions. Specifically, alerting patients with loud tones reduced the tendency for right-sided stimuli to be perceived earlier than left-sided stimuli in a temporal order judgment task. Thus, increases in alertness may be sufficient to reduce or even overcome the rightward spatial bias in neglect.

The relationship between spatial neglect and lowered levels of generalized alertness led researchers to examine whether other groups, primarily defined by low levels of alertness, may be vulnerable to leftward inattention. With respect to the attention deficit hyperactivity disorder (ADHD) diagnosis, with some exceptions (BenArtsy, Glicksohn, Soroker, Margalit, & Myslobodsky, 1996), the results have been surprisingly consistent with this view (Dobler et al., 2005; Dobler, Manly, Verity, Woolrych, & Robertson, 2003; Klimkeit, Mattingley, Sheppard, Lee, & Bradshaw, 2003; Manly, Robertson, & Verity, 1997; Nigg, Swanson, & Hinshaw, 1997). For example, Sheppard, Bradshaw, Mattingley, and Lee (1999) demonstrated that the line-bisections made by boys with this diagnosis deviated to the right compared with those of a control group—a pattern consistent with relative leftward inattention. Notably, this tendency was absent when the boys were taking the stimulant, methylphenidate. Similarly, Dobler et al. (2003), working with a boy with ADHD and a pronounced neglect of left space, demonstrated that the presentation of alerting tones in a manner akin to Robertson et al. (1998) produced temporary and significant reductions in bias. In a later study, Dobler et al. (2005) demonstrated that there was a general tendency for children to show a rightward shift in attention over the course of a long, repetitive spatial task—a tendency that was more pronounced in children with ADHD (see also George, Dobler, Nicholls, & Manly, 2005).

Such suggestions that the alertness-dependent modulation of spatial bias seen in clinical groups may reflect an exaggerated version of a normal pattern have led to direct tests of this hypothesis. In one such study, Manly, Dobler, Dodds, and George (2005) asked neurologically healthy adult participants to perform repeated trials of the landmark task (this requires the judgment about which end of a prebisected line appears longer; see below). Two factors associated with lowered subjective alertness—sleep deprivation and time-on-task—both led to an apparent rightward shift in spatial attention. Fimm, Willmes, and Spijkers (2006) replicated and added to this result using a variant of the Posner cueing task, further suggesting that the results do not depend on a change in visual scanning patterns.

Although the work linking increased alertness with a leftward shift in attention in patients with left neglect may reflect a generalized improvement in symptoms, this cannot account for the effects of reduced alertness on spatial bias in healthy participants, which have consistently involved a reduction in the normally observed leftward spatial bias. In other words, reduced alertness actually leads to a more balanced lateral distribution of attention in healthy participants.

In attempting to account for this relationship and to understand whether it contributes to the disproportionate persistence of spatial neglect in patients with RH lesions relative to their left-hemisphere counterparts, Corbetta, Kincade, Lewis, Snyder, and Sapir (2005) reported the results of an ambitious functional imaging study. Eleven patients with left spatial neglect performed a Posner spatial cueing task, initially at 4 weeks poststroke and subsequently at 39 weeks poststroke.

In this task, patients viewed a central arrow which pointed either to the left or right of fixation. After the arrow, on 75% of trials, a target appeared to the same side as indicated by the arrow (validly cued target), and on the remaining 25% of trials, a target appeared to the opposite side indicated by the arrow (invalidly cued target). This task enabled the measurement of rightward spatial bias (faster reaction times to right-sided targets) as well as attentional reorienting (reaction time to invalidly cued targets), which are both useful measures of spatial impairment in neglect.

They noted that in this and previous studies, direct lesion damage to areas normally activated by the task and thought to be involved in spatial attention and visuomotor control (dorsal fronto-parietal networks) was relatively rare. Instead, they argued, neglect typically follows damage to more ventral temporo-parietal and frontal regions of the RH thought to be involved in the maintenance of alertness. Hypothesizing that this region would normally influence the more dorsal network in responding to goal-relevant events, they argued that in the case of acute neglect, activity in anatomically intact dorsal areas would be reduced during the performance of the cueing task.

In line with this hypothesis, they found that rightward spatial bias in the Posner task was associated with a hemispheric imbalance in activation in intact dorsal regions, whereby activity in the right dorsal parietal cortex was suppressed while the left dorsal parietal cortex was hyperactivated. Furthermore, by 39 weeks, significant improvements in spatial bias were associated with a rebalancing of activation across these regions.

This offers a mechanism whereby a network that modulates responsivity to novel or goal-relevant information (“alertness”) may directly influence regions engaged in spatial attention and visuomotor responses to spatial stimuli. If, as is suggested by a number of studies (Sturm et al., 1999, 2004; Paus et al., 1997; Pardo, Fox, & Raichle, 1991; Cohen & Semple, 1988; Wilkins, Shallice, & McCarthy, 1987), these functions are somewhat lateralized to the RH, it provides a mechanism whereby increases in levels of alertness might exert a spatially specific (leftward) influence over concurrent spatial attention.

There have been a number of promising attempts to investigate the potential benefits of different stimulants in patients with left spatial neglect (Malhotra, Parton, Greenwood, & Husain, 2006; Woods et al., 2006; Mukand et al., 2001; Geminiani, Bottini, & Sterzi, 1998; Grujic et al., 1998; Hurford, Stringer, & Jann, 1998; Fleet, Valenstein, Watson, & Heilman, 1987). However, the work with patients raises the same important caveats that applied to behavioral manipulations of alertness, that is, is this a general effect of symptom reduction or a spatially specific effect?

No study, as far as we know, has investigated the effects of psychostimulant drugs on the laterality of spatial bias judgments in healthy participants. In the present study, we investigated whether administration of single doses of methylphenidate or modafinil would induce a change in the pattern of responses on an hour-long version of the “Landmark” test (Milner, Brechmann, Roberts, & Forster, 1993). This task is a simple procedure in which participants are shown a horizontal line with a vertical transecting mark somewhere along its length. They are asked to judge which end of the line looks longer (or, conversely, shorter). In the variant of the task used here, for 50% of the trials the line was bisected exactly in the center. In the absence of an “even” response option, judgments about these trials form a potentially very sensitive measure of attentional bias.

In this study, participants each received an oral dose of methylphenidate 40 mg, modafinil 400 mg, or placebo, on separate days, prior to the administration of the task. Methylphenidate is a nonspecific catecholamine agonist, primarily used to treat ADHD. Modafinil is a wake-promoting substance with unclear mechanisms of action, commonly used to treat narcolepsy and excessive daytime sleepiness (Minzenberg & Carter, 2008). It has beneficial effects on cognitive function in healthy subjects (Müller, Steffenhagen, Regenthal, & Bublak, 2004; Turner et al., 2003) and in adults with ADHD (Turner, Clark, Dowson, Robbins, & Sahakian, 2004). Doses in the middle of effective and tolerable ranges for methylphenidate (10–60 mg) and modafinil (100–600 mg) were selected based on published findings in healthy volunteers and patients (Wesensten, 2006; Volkow, Fowler, Wang, Ding, & Gatley, 2002).

The simplest hypothesis would be that, given evidence linking increases in alertness with a leftward shift in attention, participants would show a change in their pattern of responses consistent with a relative leftward shift in attention in the stimulant conditions relative to the placebo condition—in other words, an increase in the already present “pseudoneglect” effect. Any differential effect of the stimulants could then form the basis—with suitable caveats about relative dose levels—for subsequent hypotheses about the underlying mechanism. However, there are good reasons why this simple hypothesis may not be supported.

The alerting effects of stimulants and their effects on cognitive task performance appear to be dependent both upon the individual and the conditions under which they are administered. There is substantial evidence that psychostimulant drugs such as methylphenidate operate according to an inverted U-shape function, whereby participants can show markedly different drug effects depending on baseline neurotransmitter levels and task demands (Cools & Robbins, 2004; Mattay et al., 2003). Thus, although increased activity and arousal are common effects of methylphenidate, it is not unusual for subjective effects to include increased anxiety and tiredness.

Here, with a healthy and predominantly young participant group in a relatively novel setting about to participate in a relatively novel task, one might expect baseline alertness levels to be high—at least for some participants. Under these circumstances, the effect of the medication on cognitive performance and subjective alertness may be minimal, or, indeed, counterintuitive. Ideally, therefore, we would want to examine the effects of the stimulants at a time when we would expect alertness levels to have dropped. Fortunately, we have reasonable evidence that such conditions are increasingly likely to be met after a long period of performing this task (e.g., Manly et al., 2005). Furthermore, in addition to examining task performance, subjective ratings of alertness were also collected periodically in this study in order to validate the effects of time-on-task on alertness.

Thus, a stronger, if more complex, hypothesis is that participants would show a rightward shift in spatial bias with time-on-task in the placebo condition, as observed by Manly et al. (2005), but that this time-related shift in bias would be reduced, or even reversed, in the drug conditions. Furthermore, we would predict that this drug effect would occur only in participants who showed a reduced decline in subjective alertness over time in these conditions.

METHODS

Participants

Eighteen healthy participants (9 men and 9 women), aged between 20 and 35 years, were recruited from the Cambridge local community, and were included after medical screening. The lower age limit was selected with the aim of excluding undergraduate students, who are not necessarily representative of the general population. The upper age limit was selected on the basis that younger participants showed a disproportionate rightward shift in spatial bias with declining alertness in the time-on-task experiment in our previous study, and one of the predictions of the present experiment concerned this rightward shift in spatial bias.

Participants had no history of psychiatric, neurological, or cardiovascular illness and no major vision or motor impairments. Participants were asked to abstain from caffeine for at least 3 hr before the test sessions. Participants received financial compensation for their participation (£150 in total). The study protocol was given a favorable opinion by the Cambridge Local Research Ethics Committee (Ref: 05/Q0108/482) and was formally exempted from clinical trial status by MHRA, the national drug licensing agency. All participants gave written informed consent.

Design

A double-blind, randomized balanced design was used. An oral dose of modafinil 400 mg or methylphenidate 40 mg or a placebo (lactose powder) in identical opaque gelatin capsules was administered on each testing day. Each participant was tested on 3 days separated by at least 1 week. For each participant, cognitive testing began 90 min after drug intake and ended 150 min after drug intake. This interval was based on the tmax (the time for each of the drugs to reach maximum concentration in the blood) and the half-life (the time it takes for one half of the original dose to leave the body) of both drugs. The tmax of both drugs is between 90 and 120 min. The half-life of methylphenidate is 2 to 3 hr and the half-life of modafinil is 10 to 12 hr. Thus, the time interval was selected to ensure that both drugs would reach their tmax during the testing period (allowing for some variation among participants) but that the testing period would end before the half-life of methylphenidate was reached.

Here we refer to the time of drug administration as t0, the time 90 min after drug administration when testing began as t1, and the time 150 min after drug administration when testing ended as t2. A Visual Analogue Scale (VAS), measuring subjective alertness on a scale from 1 to 100 was administered thrice in each session—once at baseline (t0), once before testing (t1), and once after testing (t2).

Landmark Task

Spatial bias was investigated using the landmark task. The task procedure was as follows:

Firstly, a question appeared on the screen. This could be either “which end is longer?” or “which end is shorter?” The question alternated between these two alternatives from one trial of each task to the next trial of that task. The question remained on the screen for 2000 msec. After the question disappeared, a pattern mask was presented for 1000 msec and then the target stimuli (a 200 mm × 1 mm horizontal line bisected by a 17 mm × 2 mm vertical line) appeared. The bisecting vertical line could be bisected either in the center (50% of trials), 5 mm to the left of center (25% of trials) or 5 mm to the right of center (25% of trials). The line remained on the screen for 1000 msec, then disappeared and was replaced by a pattern mask, which remained on the screen for 1000 msec.

The question was repeated after presentation of the target stimuli, at which point participants responded, pressing the right mouse key for a “right” response and the left mouse key for a “left” response. Participants were told to take as long as they wanted over responding. The repeated question remained on the screen until the participant responded. After the participant responded, a mask appeared for 1000 msec and the next trial followed automatically.

The first 10 trials of each session were practice trials and were not included in the final analysis. Participants were told before the experiment that the deviations from center were sometimes very subtle, and were told not to guess, but to base their answers on the perceptual evidence available. Within each task, the order of conditions was randomized across the whole experiment. Because one of the main predictions concerned time-on-task effects, the experiment lasted 1 hr. Thus, different participants completed different total numbers of trials in this period of time.

RESULTS

Subjective Alertness Ratings

The main hypothesis of the study concerned the effects of time-on-task related changes in alertness on spatial bias. Therefore, the participants' VAS subjective alertness ratings were first examined to establish whether alertness declined with time and whether the stimulants offset or even reversed this decline between t1 (before the landmark task) and t2 (after the landmark task). Mean VAS subjective alertness ratings across all 18 participants are shown in Figure 1. Percentage values were ArcSin transformed for statistical analysis.

Figure 1. 

Average VAS subjective alertness ratings for all three conditions at the three time points: t0 = around dosing; t1 = immediately before landmark task; t2 = immediately after landmark task. Ratings are transformed into a percentage score based on the position of the participant's mark along the horizontal line. 1 = “very sleepy,” 100 = “very alert.”

Figure 1. 

Average VAS subjective alertness ratings for all three conditions at the three time points: t0 = around dosing; t1 = immediately before landmark task; t2 = immediately after landmark task. Ratings are transformed into a percentage score based on the position of the participant's mark along the horizontal line. 1 = “very sleepy,” 100 = “very alert.”

A 3 × 2 repeated measures ANOVA with condition (placebo, methylphenidate, or modafinil) and time (t1 or t2) as factors was performed on the ArcSin transformed VAS ratings. This revealed a significant main effect of condition [F(2, 16) = 8, p < .01], and a significant main effect of time [F(1, 17) = 23, p < .001], but no significant interaction between condition and time [F(2, 16) = 2, p = .17]. As shown in Figure 1, participants reported being more drowsy overall in the placebo condition relative to the drug conditions, and participants reported being more drowsy at t2 (after the landmark task) than at t1 (before the landmark task) in all three conditions [placebo: t(17) = 5.3, p < .001; methylphenidate: t(17) = 2.1, p < .05; modafinil: t(17) = 2.2, p < .05].

Closer examination revealed substantial interparticipant variation in subjective alertness ratings which accounts for the lack of a statistically significant interaction. Figure 2 shows the difference in time-on-task changes in alertness between placebo and drug conditions for each participant individually. Five participants showed a greater increase in drowsiness between t1 and t2 in the methylphenidate condition than in the placebo condition. Similarly, seven participants showed a greater increase in drowsiness between t1 and t2 in the modafinil condition than in the placebo condition. This variability may be due to, as discussed, a combination of genetic influences and circumstantial factors.

Figure 2. 

Difference in time-on-task-related changes in alertness between the placebo and drug conditions for modafinil (left) and methylphenidate (right). For each participant (numbered along the x-axis), we calculated the difference between the reduction in alertness with time-on-task for the placebo condition (t1t2 placebo VAS score) and the reduction in alertness with time-on-task for each drug condition (t1t2 drug VAS score). This difference score is represented here on the y-axis. Positive scores indicate participants who became more drowsy over time in the placebo condition than in the drug condition, and negative scores indicate participants who became more drowsy over time in the drug condition than in the placebo condition.

Figure 2. 

Difference in time-on-task-related changes in alertness between the placebo and drug conditions for modafinil (left) and methylphenidate (right). For each participant (numbered along the x-axis), we calculated the difference between the reduction in alertness with time-on-task for the placebo condition (t1t2 placebo VAS score) and the reduction in alertness with time-on-task for each drug condition (t1t2 drug VAS score). This difference score is represented here on the y-axis. Positive scores indicate participants who became more drowsy over time in the placebo condition than in the drug condition, and negative scores indicate participants who became more drowsy over time in the drug condition than in the placebo condition.

The lack of a significant interaction between condition and time makes it difficult to assess the effects of a change in alertness over time on spatial bias—in fact, the main hypothesis rests on such an interaction between condition and time being present. For this reason, participants who showed an unexpected greater increase in drowsiness between t1 and t2 in the drug conditions than in the placebo condition were excluded from the subsequent analysis of spatial bias results. Alertness ratings from each condition were subsequently analyzed in two separate groups—one group consisting of those participants who showed the expected difference between modafinil and placebo (modafinil group) and another group who showed the expected difference between methylphenidate and placebo (methylphenidate group). Repeated measures ANOVAs confirmed a significant interaction between condition and time in the methylphenidate group [F(1, 12) = 9.6, p < .05] and a significant interaction between condition and time in the modafinil group [F(1, 10) = 16.4, p < .05]. In the methylphenidate group, participants became more drowsy between t1 and t2 in the placebo condition [t(12) = 5.5, p < .05], but not in the methylphenidate condition [t(12) = 1.0, p = .3]. In the modafinil group, participants also became more drowsy in the placebo condition [t(10) = 6.5, p < .05], but not in the modafinil condition [t(10) = 1.1, p = .29].

Spatial Bias

Error rates on trials bisected to the left and right of center were very low. On average, participants responded correctly on >95% of these trials. Only trials in which the line was bisected in the center were analyzed, as this provides the most sensitive measure of spatial bias. Trials were divided into a first half (Block 1) and a second half (Block 2) in order to measure time-on-task effects. However, it is important to note that participants were not aware of this division—for them each testing session was a single, unbroken run of trials.

To calculate rightward bias in each block (leftward bias would be entirely reciprocal and the choice is arbitrary), trials with equivalent responses consistent with an attentional bias to the right (e.g., “right longer” and “left shorter”) were first summed and then divided by the total number of trials. This proportion was then ArcSin transformed for subsequent statistical analysis. Two separate analyses were performed because different participants were excluded from the methylphenidate and modafinil conditions based on their subjective alertness ratings—one comparing spatial bias in the methylphenidate and placebo condition, and another comparing spatial bias in the modafinil and placebo condition. Two 2 × 2 repeated measures ANOVAs were therefore carried out on the spatial bias scores, with condition (placebo or drug) and block (1 or 2) as factors.

In the modafinil group, there was a significant interaction between condition (modafinil vs. placebo) and block (1 vs. 2) in the ANOVA [F(1, 10) = 6.7, p < .05; see Figure 3]. There were no main effects of condition [F(1, 10) = 1.3, p = .3] or block [F(1, 10) = 0.26, p = .62]. This interaction crucially relies on the comparison of the two conditions. When each condition is considered separately using t-test analyses of bias scores in Blocks 1 and 2, these do not reach significance [placebo condition Block 1 vs. Block 2: t(10) = 1.2, p = .27; modafinil condition Block 1 vs. Block 2: t(10) = 1.5, p = .17].

Figure 3. 

Rightward spatial bias scores for Block 1 and Block 2 of the landmark task, averaged across participants who showed the expected maintenance of alertness over time in the modafinil condition (left) and methylphenidate condition (right) relative to the placebo condition. The rightward bias score was calculated by adding together the number of “left shorter” and “right longer” responses on center-bisected trials and dividing this by the total number of center-bisected trials. This number reflects the proportion of trials on which the left end of the line was judged as shorter than the right end (i.e., attention was biased toward the right end of the line). A higher number indicates a greater bias toward the right.

Figure 3. 

Rightward spatial bias scores for Block 1 and Block 2 of the landmark task, averaged across participants who showed the expected maintenance of alertness over time in the modafinil condition (left) and methylphenidate condition (right) relative to the placebo condition. The rightward bias score was calculated by adding together the number of “left shorter” and “right longer” responses on center-bisected trials and dividing this by the total number of center-bisected trials. This number reflects the proportion of trials on which the left end of the line was judged as shorter than the right end (i.e., attention was biased toward the right end of the line). A higher number indicates a greater bias toward the right.

In the methylphenidate group, there was no interaction between condition and block [F(1, 12) = 0.07, p = .8], and no main effects of condition [F(1, 12) = 1.4, p = .26] or block [F(1, 12) = 1, p = .33]. The difference in spatial bias between Block 1 and Block 2 in the placebo condition did not reach significance [t(12) = 1.2, p = .24], and there was no difference in spatial bias between Block 1 and Block 2 in the methylphenidate condition [t(12) = 0.4, p = .7].

The spatial bias scores from the excluded participants were also analyzed with t tests. In both the modafinil and methylphenidate groups, spatial bias scores in the excluded participants showed a small nonsignificant shift toward the right between Block 1 and Block 2 in both the placebo and drug conditions. In the modafinil group, the mean increase in rightward spatial bias score between Block 1 and Block 2 in the placebo condition was 7.4 (SD = 14.6) [t(6) = 1.4, p = .2], and in the modafinil condition was 10.2 (SD = 17.7) [t(6) = 1.5, p = .17]. In the methylphenidate group, the mean increase in rightward spatial bias score between Block 1 and Block 2 in the placebo condition was 9.7 (SD = 15.8) [t(4) = 1.4, p = .23] and in the methylphenidate condition was 7.4 (SD = 6.6) [t(4) = 2.4, p = .07].

DISCUSSION

In this study, we examined the effects of psychostimulant-induced manipulations of alertness on changes in spatial bias over time in healthy participants. There are, as discussed, well-established individual differences in response to stimulant medication based on genetic and situational factors. Although our data do not speak to the underlying causes of variable responses in the participants tested here, for the purposes of this study, the important point is that a sufficient number of participants showed the expected alerting effects of the drugs in their self-reports for us to examine the relationship between drug-induced changes in alertness on spatial bias.

In psychostimulant-alerted participants, we observed the hypothesized opposing effects of time-on-task and modafinil. This was consistent with a direct modulatory link between alertness and spatial bias. These effects are consistent with the hypothesis that there is a direct link between “alertness” and spatial bias. It is important to stress that the absolute magnitude of these shifts was, as expected from previous research in the healthy population, small. In contrast, we observed no effect of methylphenidate on spatial bias.

What is the neural basis of these alertness-dependent shifts in the direction of spatial attention? There is a substantial body of evidence, from functional imaging and lesion studies, linking nonspatial functions such as sustained attention and alertness with neural activity in the RH (Sturm et al., 1999, 2004; Paus et al., 1997; Pardo et al., 1991; Cohen & Semple, 1988; Wilkins et al., 1987). Activity in these RH-based areas has been observed to undergo dynamic changes in intensity as performance fluctuates over time, both within a task (Paus et al., 1997) and over an extended period of recovery after a lesion (Corbetta et al., 2005). Shifts in the direction of spatial bias over time may be a consequence of subtle changes in the relative balance of hemispheric activation resulting from such changes in neural activation. Thus, the effect of modafinil may be to redress, or reverse, the imbalance in hemispheric activation by increasing levels of neural activity in an RH-based alertness system.

This explanation is, of course, speculative because there are, at present, no published findings on the effects of modafinil on cortical BOLD signal. However, the hypothesis that changes in the direction of spatial bias can result from altered processing in systems which do not directly mediate spatial attention is consistent with a view of spatial attention recently described by Duncan (2006). According to this view, changes in spatial bias do not necessarily depend on dysfunction or damage in a specialized system for spatial attention, but can arise from an imbalance in hemispheric activation caused by changes in activation at multiple different levels of processing. Thus, spatial bias is seen as an emergent property of a system in which multiple cognitive systems interact competitively to produce a unified conscious experience.

An alternative explanation for the effects of modafinil on spatial bias is that the drug increases overall activity for performance optimization. Indeed, in Block 1, participants showed a stronger bias to the left side in the placebo condition than in the modafinil condition. This could be interpreted as showing that participants were more able to distribute their responses evenly between left-shorter and right-shorter judgments on center-bisected line trials, effectively optimizing their strategy in the absence of any objective measure of success. However, it is worth noting that the ability to employ this strategy may be dependent on the ability to perceive the relative length of the two ends of the line more accurately in the modafinil condition. Thus, although this explanation would rule out a strict hemispheric account of the results, it would not rule out the possibility that modafinil may exert beneficial effects on spatial attention. Further studies would be required to separate out fully strategy optimization effects and directional effects on spatial bias.

Unlike modafinil, methylphenidate exerted no consistent effect on spatial bias in the present study. In terms of this difference, there is substantial evidence that, despite its generally positive effects on cognitive function in some clinical groups, methylphenidate can exert rather weak, or even negative, effects on cognition in participants from the nonclinical population (Bray et al., 2004; Rogers et al., 1999; Elliott et al., 1997). This pattern appears to be mirrored at the level of neural activation. Methylphenidate (and amphetamines) has, for example, been observed to reduce the BOLD signal in areas associated with alertness such as the dorsolateral prefrontal cortex and the parietal cortex in healthy participants (Mattay et al., 2003; Mehta et al., 2000) while producing BOLD increases in groups thought to have pathologically lowered alertness, such as children with ADHD (Vaidya, Austin, Kikkorian, Ridlehuber, & Glover, 1998). This may account for the reduction in rightward spatial bias following methylphenidate administration in children diagnosed with ADHD (Sheppard et al., 1999) and in adults with left spatial neglect but the absence of such an effect here.

The differential effects of methylphenidate and modafinil in the present study may be due to the different neuropharmacological profiles of the two drugs. It is well established that methylphenidate blocks the transporters of the catecholamines dopamine and noradrenaline (Seeman & Madras, 1998), and increasing evidence suggests that modafinil also modulates catecholamine neurotransmission (for a review, see Minzenberg & Carter, 2008). However, the mechanisms of action of modafinil and methylphenidate may also diverge in important respects.

Although methylphenidate increases concentrations of dopamine by blocking its reuptake in the striatum, there is increasing evidence that modafinil affects cortical function (Dauvilliers, Neidhart, Billiard, & Tafti, 2002; de Saint Hilaire, Orosco, Rouch, Blanc, & Nicolaidis, 2001; Simon, Hemet, Ramassamy, & Costentin, 1995; De Sereville, Boer, Rambert, & Duteil, 1994). This may be due to preferential effects of modafinil on the noradrenaline system, consistent with the well-established finding that noradrenaline receptors are abundant in the prefrontal cortex but are virtually absent from the striatum (e.g., Herregodts, Ebinger, & Michotte, 1991).

Evidence that dopamine and noradrenaline are differentially involved in the alerting effects of methylphenidate and modafinil comes from a recent study investigating the effects of these two drugs on the performance of rats on a widely used test of impulsivity, the stop-signal reaction time task (SSRT). Eagle, Tufft, Goodchild, and Robbins (2007)found that administration of the mixed D1/D2 dopamine receptor antagonist cis-flupenthixol led to an increase in go-trial reaction times, and that these effects were antagonized by methylphenidate but not modafinil. This suggests that effects of methylphenidate and modafinil on alertness are under the control of different neurotransmitter systems, such that methylphenidate-induced increases in alertness are mediated by changes in the dopamine system and modafinil-induced increases in alertness are mediated by changes in the noradrenaline system. Thus, effects of modafinil on spatial bias may be due to noradrenaline-mediated modulation of prefrontal cortical activity.

Impairments in spatial bias in neglect most commonly result from cortical lesions and functional imaging studies have consistently localized the systems controlling attention and alertness to RH cortical areas (Sturm et al., 1999, 2004; Paus et al., 1997; Pardo et al., 1991; Cohen & Semple, 1988). Thus, it is reasonable to suppose that the small lateralization of spatial bias commonly observed in the healthy population is also due to a cortical hemispheric imbalance, and that rebalancing of cortical activity will be most effective with drugs such as modafinil that operate via cortical, rather than subcortical, mechanisms of action.

However, the situation is further complicated by the issue of dose. Our dose selection was based on existing data on equivalent general effects of the two agents on subjective alertness—and this indeed is reflected in the subjective ratings that we observed (see Figure 1). Such ratings are likely, of course, to be influenced by multiple factors and it remains possible that, in some key effect necessary for changes in spatial bias, the doses are not equivalent. Whether greater or lesser doses of methylphenidate would have a similar effect remains to be tested.

Previous studies in patients with left unilateral spatial neglect have shown that the severity of leftward inattention can be modulated by fluctuations in alertness (Dodds, Dove, Warburton, & Manly, submitted; Robertson et al., 1998). Recently, several studies have also demonstrated alertness-dependent shifts in spatial bias in healthy participants (Fimm et al., 2006; Manly et al., 2005), suggesting that the effects of alertness on spatial bias in patients may reflect a direct modulatory influence of alertness on spatial bias. Taken together, these studies suggest that pharmacological manipulation of the alertness system may provide one route toward facilitation of recovery in neglect.

Indeed, several studies have investigated the ability of pharmacological agents to ameliorate spatial bias in patients with neglect (Müller, 2008; Malhotra et al., 2006; Woods et al., 2006; Mukand et al., 2001; Geminiani et al., 1998; Grujic et al., 1998; Hurford et al., 1998; Fleet et al., 1987), and have, with the exception of one study (Grujic et al., 1998), found generally encouraging results. However, most of these studies have tested either a single patient or a very small sample of patients, making it difficult to generalize results. Moreover, the only study that examined the effects of modafinil on spatial bias tested a single patient with a left-hemisphere lesion (Woods et al., 2006). The results of the present study lead to the prediction that modafinil will exert the most beneficial effects on spatial bias after RH lesions.

In summary, a significant interaction was observed consistent with the stimulant effects of modafinil resisting a time-on-task-related rightward shift in spatial bias—in those who showed a subjective alerting effect of the drug. In contrast, no effect of methylphenidate on spatial bias was detected. Future studies should explore the effects of modafinil on the lateralization of neural activity in tasks requiring alertness and sustained attention.

Reprint requests should be sent to Chris Dodds, Behavioural and Clinical Neuroscience Institute, Department of Experimental Psychology, University of Cambridge, Downing Site, CB2 3EB, UK, or via e-mail: cd317@cam.ac.uk.

REFERENCES

REFERENCES
BenArtsy
,
A.
,
Glicksohn
,
J.
,
Soroker
,
N.
,
Margalit
,
M.
, &
Myslobodsky
,
M.
(
1996
).
An assessment of hemineglect in children with attention-deficit hyperactivity disorder.
Developmental Neuropsychology
,
12
,
271
281
.
Bray
,
C. L.
,
Cahill
,
K. S.
,
Oshier
,
J. T.
,
Peden
,
C. S.
,
Theriaque
,
D. W.
,
Flotte
,
T. R.
,
et al
(
2004
).
Methylphenidate does not improve cognitive function in healthy sleep-deprived young adults.
Journal of Investigative Medicine
,
52
,
192
201
.
Cohen
,
R. M.
, &
Semple
,
W. E.
(
1988
).
Functional localization of sustained attention.
Neuropsychiatry, Neuropsychology and Behavioural Neurology
,
1
,
3
20
.
Cools
,
R.
, &
Robbins
,
T. W.
(
2004
).
Chemistry of the adaptive mind.
Philosophical Transactions—Royal Society: Mathematical, Physical and Engineering Sciences
,
362
,
2871
2888
.
Corbetta
,
M.
,
Kincade
,
M. J.
,
Lewis
,
C.
,
Snyder
,
A. Z.
, &
Sapir
,
A.
(
2005
).
Neural basis and recovery of spatial attention deficits in spatial neglect.
Nature Neuroscience
,
8
,
1603
1610
.
Dauvilliers
,
Y.
,
Neidhart
,
E.
,
Billiard
,
M.
, &
Tafti
,
M.
(
2002
).
Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil.
Pharmacogenomics Journal
,
2
,
65
68
.
de Saint Hilaire
,
Z.
,
Orosco
,
M.
,
Rouch
,
C.
,
Blanc
,
G.
, &
Nicolaidis
,
S.
(
2001
).
Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: A microdialysis study in rats.
NeuroReport
,
12
,
3533
3537
.
De Sereville
,
J. E.
,
Boer
,
C.
,
Rambert
,
F. A.
, &
Duteil
,
J.
(
1994
).
Lack of pre-synaptic dopaminergic involvement in modafinil activity in anaesthetized mice: In vivo voltammetry studies.
Neuropharmacology
,
33
,
755
761
.
Dobler
,
V. B.
,
Anker
,
S.
,
Gilmore
,
J.
,
Robertson
,
I. H.
,
Atkinson
,
J.
, &
Manly
,
T.
(
2005
).
Asymmetric deterioration of spatial awareness with diminishing levels of alertness in normal children and children with ADHD.
Journal of Child Psychology and Psychiatry
,
46
,
1230
1248
.
Dobler
,
V. B.
,
Manly
,
T.
,
Verity
,
C.
,
Woolrych
,
J.
, &
Robertson
,
I. H.
(
2003
).
Modulation of spatial attention in a child with developmental unilateral neglect.
Developmental Medicine and Child Neurology
,
45
,
282
288
.
Dodds
,
C. M.
,
Dove
,
A.
,
Warburton
,
E.
, &
Manly
,
T.
(
submitted
).
Spontaneous fluctuations in alertness modulate the severity of unilateral spatial neglect: Two demonstrations.
Duncan
,
J.
(
2006
).
EPS Mid-Career Award 2004: Brain mechanisms of attention.
Quarterly Journal of Experimental Psychology
,
59
,
2
27
.
Eagle
,
D. M.
,
Tufft
,
M. R.
,
Goodchild
,
H. L.
, &
Robbins
,
T. W.
(
2007
).
Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixol.
Psychopharmacology (Berlin)
,
192
,
193
206
.
Elliott
,
R.
,
Sahakian
,
B. J.
,
Matthews
,
K.
,
Bannerjea
,
A.
,
Rimmer
,
J.
, &
Robbins
,
T. W.
(
1997
).
Effects of methylphenidate on spatial working memory and planning in healthy young adults.
Psychopharmacology (Berlin)
,
131
,
196
206
.
Fimm
,
B.
,
Willmes
,
K.
, &
Spijkers
,
W.
(
2006
).
The effect of low arousal on visuo-spatial attention.
Neuropsychologia
,
44
,
1261
1268
.
Fleet
,
W. S.
,
Valenstein
,
E.
,
Watson
,
R. T.
, &
Heilman
,
K. M.
(
1987
).
Dopamine agonist therapy for neglect in humans.
Neurology
,
37
,
1765
1770
.
Geminiani
,
G.
,
Bottini
,
G.
, &
Sterzi
,
R.
(
1998
).
Dopaminergic stimulation in unilateral neglect.
Journal of Neurology, Neurosurgery and Psychiatry
,
65
,
344
347
.
George
,
M.
,
Dobler
,
V. B.
,
Nicholls
,
E.
, &
Manly
,
T.
(
2005
).
Spatial awareness, alertness and ADHD: The re-emergence of unilateral neglect with time-on-task.
Brain and Cognition
,
57
,
264
275
.
Grujic
,
Z.
,
Mapstone
,
M.
,
Gitelman
,
D. R.
,
Johnson
,
N.
,
Weintraub
,
S.
,
Hays
,
A.
,
et al
(
1998
).
Dopamine agonists reorient visual exploration away from the neglected hemispace.
Neurology
,
51
,
1395
1398
.
Herregodts
,
P.
,
Ebinger
,
G.
, &
Michotte
,
Y.
(
1991
).
Distribution of monoamines in human brain: Evidence for neurochemical heterogeneity in subcortical as well as in cortical areas.
Brain Research
,
542
,
300
306
.
Hjaltason
,
H.
,
Tegner
,
R.
,
Tham
,
K.
,
Levander
,
M.
, &
Ericson
,
K.
(
1996
).
Sustained attention and awareness of disability in chronic neglect.
Neuropsychologia
,
34
,
1229
1233
.
Hurford
,
P.
,
Stringer
,
A. Y.
, &
Jann
,
B.
(
1998
).
Neuropharmacologic treatment of hemineglect: A case report comparing bromocriptine and methylphenidate.
Archives of Physical Medicine and Rehabilitation
,
79
,
346
349
.
Husain
,
M.
,
Shapiro
,
S. K.
,
Martin
,
J.
, &
Kennard
,
C.
(
1997
).
Abnormal temporal dynamics of visual attention in spatial neglect patients.
Nature
,
385
,
154
156
.
Klimkeit
,
E. I.
,
Mattingley
,
J. B.
,
Sheppard
,
D. M.
,
Lee
,
P.
, &
Bradshaw
,
J. L.
(
2003
).
Perceptual asymmetries in normal children and children with attention deficit/hyperactivity disorder.
Brain and Cognition
,
52
,
205
215
.
Malhotra
,
P. A.
,
Parton
,
A. D.
,
Greenwood
,
R.
, &
Husain
,
M.
(
2006
).
Noradrenergic modulation of space exploration in visual neglect.
Annals of Neurology
,
59
,
186
190
.
Manly
,
T.
,
Dobler
,
V. B.
,
Dodds
,
C. M.
, &
George
,
M. A.
(
2005
).
Rightward shift in spatial awareness with declining alertness.
Neuropsychologia
,
43
,
1721
1728
.
Manly
,
T.
,
Robertson
,
I.
, &
Verity
,
C.
(
1997
).
Developmental unilateral visual neglect: A single case study.
Neurocase
,
3
,
19
29
.
Mattay
,
V. S.
,
Goldberg
,
T. E.
,
Fera
,
F.
,
Hariri
,
A. R.
,
Tessitore
,
A.
,
Egan
,
M. F.
,
et al
(
2003
).
Catechol O-methyltransferase val158–met genotype and individual variation in the brain response to amphetamine.
Proceedings of the National Academy of Sciences, U.S.A.
,
100
,
6186
6191
.
Mehta
,
M. A.
,
Owen
,
A. M.
,
Sahakian
,
B. J.
,
Mavaddat
,
N.
,
Pickard
,
J. D.
, &
Robbins
,
T. W.
(
2000
).
Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain.
Journal of Neuroscience
,
20
,
RC65
.
Milner
,
A. D.
,
Brechmann
,
M.
,
Roberts
,
R. C.
, &
Forster
,
S. V.
(
1993
).
Line bisection errors in visual neglect: Misguided action or size distortion?
Neuropsychologia
,
31
,
39
49
.
Minzenberg
,
M. J.
, &
Carter
,
C. S.
(
2008
).
Modafinil: A review of neurochemical actions and effects on cognition.
Neuropsychopharmacology
,
33
,
1477
1502
.
Mukand
,
J. A.
,
Guilmette
,
T. J.
,
Allen
,
D. G.
,
Brown
,
L. K.
,
Brown
,
S. L.
,
Tober
,
K. L.
,
et al
(
2001
).
Dopaminergic therapy with carbidopa L-dopa for left neglect after stroke: A case series.
Archives of Physical Medicine and Rehabilitation
,
82
,
1279
1282
.
Müller
,
U.
(
2008
).
Pharmacological treatment.
In S. F. Cappa, J. Abutalebi, J.-F. Démonet, P. Fletcher, & P. Garrard (Eds.),
Cognitive neurology: A clinical textbook
(pp.
475
498
).
Oxford
:
Oxford University Press
.
Müller
,
U.
,
Steffenhagen
,
N.
,
Regenthal
,
R.
, &
Bublak
,
P.
(
2004
).
Effects of modafinil on working memory processes in humans.
Psychopharmacology (Berlin)
,
177
,
161
169
.
Nigg
,
J. T.
,
Swanson
,
J. M.
, &
Hinshaw
,
S. P.
(
1997
).
Covert spatial attention in boys with attention deficit hyperactivity disorder: Lateral effects, methylphenidate response and results for parents.
Neuropsychologia
,
35
,
165
176
.
Pardo
,
J. V.
,
Fox
,
P. T.
, &
Raichle
,
M. E.
(
1991
).
Localization of a human system for sustained attention by positron emission tomography.
Nature
,
349
,
61
64
.
Paus
,
T.
,
Zatorre
,
R.
,
Hofle
,
N.
,
Caramonos
,
Z.
,
Gotman
,
J.
,
Petrides
,
M.
,
et al
(
1997
).
Time related changes in neural systems underlying attention and arousal during the performance of an auditory vigilance task.
Journal of Cognitive Neuroscience
,
3
,
392
408
.
Robertson
,
I.
,
Manly
,
T.
,
Beschin
,
N.
,
Daini
,
R.
,
Haeske-Derwick
,
H.
,
Homberg
,
V.
,
et al
(
1997
).
Auditory sustained attention is a marker of unilateral spatial neglect.
Neuropsychologia
,
13
,
1527
1532
.
Robertson
,
I. H.
,
Mattingley
,
J. B.
,
Rorden
,
C.
, &
Driver
,
J.
(
1998
).
Phasic alerting of neglect patients overcomes their spatial deficit in visual awareness.
Nature
,
395
,
169
172
.
Rogers
,
R. D.
,
Blackshaw
,
A. J.
,
Middleton
,
H. C.
,
Matthews
,
K.
,
Hawtin
,
K.
,
Crowley
,
C.
,
et al
(
1999
).
Tryptophan depletion impairs stimulus–reward learning while methylphenidate disrupts attentional control in healthy young adults: Implications for the monoaminergic basis of impulsive behaviour.
Psychopharmacology (Berlin)
,
146
,
482
491
.
Seeman
,
P.
, &
Madras
,
B. K.
(
1998
).
Anti-hyperactivity medication: Methylphenidate and amphetamine.
Molecular Psychiatry
,
3
,
386
396
.
Shapiro
,
K.
,
Hillstrom
,
A. P.
, &
Husain
,
M.
(
2002
).
Control of visuotemporal attention by inferior parietal and superior temporal cortex.
Current Biology
,
12
,
1320
1325
.
Sheppard
,
D. M.
,
Bradshaw
,
J. L.
,
Mattingley
,
J. B.
, &
Lee
,
P.
(
1999
).
Effects of stimulant medication on the lateralisation of line bisection judgements of children with attention deficit hyperactivity disorder.
Journal of Neurology, Neurosurgery and Psychiatry
,
66
,
57
63
.
Simon
,
P.
,
Hemet
,
C.
,
Ramassamy
,
C.
, &
Costentin
,
J.
(
1995
).
Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice.
European Neuropsychopharmacology
,
5
,
509
514
.
Sturm
,
W.
,
Longoni
,
F.
,
Fimm
,
B.
,
Dietrich
,
T.
,
Weis
,
S.
,
Kemna
,
S.
,
et al
(
2004
).
Network for auditory intrinsic alertness: A PET study.
Neuropsychologia
,
42
,
563
568
.
Sturm
,
W.
,
Simone
,
A.
,
Krause
,
B.
,
Specht
,
K.
,
Hesselmann
,
V.
,
Radermacher
,
I.
,
et al
(
1999
).
Functional anatomy of intrinsic alertness: Evidence for a fronto-parietal–thalamic–brainstem network in the right hemisphere.
Neuropychologia
,
37
,
797
805
.
Turner
,
D. C.
,
Clark
,
L.
,
Dowson
,
J.
,
Robbins
,
T. W.
, &
Sahakian
,
B. J.
(
2004
).
Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder.
Biological Psychiatry
,
55
,
1031
1040
.
Turner
,
D. C.
,
Robbins
,
T. W.
,
Clark
,
L.
,
Aron
,
A. R.
,
Dowson
,
J.
, &
Sahakian
,
B. J.
(
2003
).
Cognitive enhancing effects of modafinil in healthy volunteers.
Psychopharmacology
,
165
,
260
269
.
Vaidya
,
C.
,
Austin
,
G.
,
Kikkorian
,
G.
,
Ridlehuber
,
H.
, &
Glover
,
D.
(
1998
).
Selective deficits of methylphenidate in attention deficit hyperactivity disorder: A functional magnetic resonance study.
Proceedings of the National Academy of Sciences, U.S.A.
,
95
,
14494
14499
.
Volkow
,
N. D.
,
Fowler
,
J. S.
,
Wang
,
G. J.
,
Ding
,
Y. S.
, &
Gatley
,
S. J.
(
2002
).
Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in humans: Results from imaging studies.
European Neuropsychopharmacology
,
12
,
557
566
.
Wesensten
,
N. J.
(
2006
).
Effects of modafinil on cognitive performance and alertness during sleep deprivation.
Current Pharmaceutical Design
,
12
,
2457
2471
.
Wilkins
,
A. J.
,
Shallice
,
T.
, &
McCarthy
,
R.
(
1987
).
Frontal lesions and sustained attention.
Neuropsychologia
,
25
,
359
365
.
Woods
,
A. J.
,
Mennemeier
,
M.
,
Garcia-Rill
,
E.
,
Meythaler
,
J.
,
Mark
,
V. W.
,
Jewel
,
G. R.
,
et al
(
2006
).
Bias in magnitude estimation following left hemisphere injury.
Neuropsychologia
,
44
,
1406
1412
.