Neglect patients behave as if the left part of the world had ceased to exist. As a consequence, both in clinical tasks and in many daily life activities, the patient’s behavior is usually biased toward the right side of space. It has also been demonstrated that neglect for proximal space (i.e., space within reaching distance) can be dissociated from neglect for distal space (space beyond reaching distance) (Halligan and Marshall, 1991; Cowey et al., 1994, 1999; Vuilleumier et al., 1998). In addition, near and far space representations were found to be dynamic, rather than static. Neurophysiological (Iriki et al., 1996) and neuropsychological studies (Berti and Frassinetti, 2000; Berti et al., 2002; Neppi-Mòdona et al., 2007) have shown that far space can me remapped as near, and near space as far, depending on the tool/action used by the patient to reach objects located in near and far space, respectively. Furthermore, among the functions that can be impaired in neglect there is walking, with patients showing a lateral deviation of the walking trajectory. Published research is contradictory regarding the direction of the lateral deviation, reporting both leftward and rightward deviations (Robertson et al., 1994; Tromp et al., 1995; Berti et al., 2002; Huitema et al., 2006; Turton et al., 2009). Leftward deviations have been found to be related to milder neglect (Tromp et al., 1995) or to a better preserved walking ability (Huitema et al., 2006).

Berti et al. (2002) have shown that neglect patients with more severe neglect in far than in near space produce a bisection error to the right (in the case of left neglect) of the true center of the line, when explicitly asked to walk across lines fixed to the floor in far space (3 m away). On the contrary, when the line was located in near space (1 m), the bisection error was less severe or even absent. This error pattern paralleled the bisection error made by the same patients in a line bisection task in near and far space using a projection light pen. Interestingly, patients’ walking trajectories were rectilinear when the line was located in far space. This suggested that the spatial representation activated at the beginning of the walking path (a far space representation, more severely impaired) was not updated during walking. Indeed, if this had been the case, a near (less impaired) space representation should have been activated while approaching the line: as a consequence, the trajectory would have been corrected resulting in a curvilinear path and the final error would have been reduced. The absence of spatial remapping during walking may be responsible for the collisions with objects and people occurring to neglect patients in their everyday life.

Although many different rehabilitative techniques have been effective in transitorily improving neglect, they often failed to produce a long-lasting beneficial effect. Some years ago, however, Rossetti et al. (1998) observed for the first time that wearing goggles fitted with prismatic lenses that shift the visual field 10°to the right may improve neglect in conventional neuropsychological tests performed in the patient’s peripersonal space. The positive result was already evident 5 min after prismatic adaptation (PA), lasting up to 2 h. Subsequent studies have shown that the effect of PA can be relatively long-lasting, being still effective up to 6 months post treatment (Frassinetti et al., 2002; Serino et al., 2006, 2007; Rusconi and Carelli, 2012).

In the present study we explored the effect of PA on the walking trajectory of a neglect patient with more severe neglect in far than in near space who was asked to repeatedly bisect a fixed line on the floor by walking across it. When neglect is more severe in far than in near space, two predictions can be made (Berti et al., 2002): (1) space is not remapped: the walking trajectory is rectilinear and the severity of neglect in far space determines the final bisection error; (2) space is remapped: the walking trajectory is curvilinear and the final bisection error is smaller because it is influenced by the near space representation (less compromised) activated while approaching the target. In both instances, if prism adaptation has a rehabilitative effect on the walking trajectory, it should produce a reduction of the final bisection error, either by improving the far space representation at the beginning of walking [in both cases 1 and 2), or by refining the remapping of far space into near space during walking (in case 2) only].

In the following analyses, the dependent variables (bisection errors in reaching/pointing tasks and in walking tasks computed prior to each PA session) are expressed as % deviation with respect to half line length – positive values indicate a rightward error, negative values indicate a leftward error. In order to investigate the presence of dissociations between near and far space neglect, we evaluated bisection errors both in near and in far space. The effect of PA, instead, was evaluated in far space only. The reason is twofold: (1) neglect was absent in the manual bisection task in near space (the bisection error (−3.0%) was not significantly different from the null value in a One Sample t test: t₉ = −1.30; p = 0.23); (2) in the walking bisection task it is possible to investigate the occurrence of spatial remapping of gait trajectory only when the line is located in far space. A summary of the results is reported in the subsequent Tables 2 and 3.

As a premise, we must point out that this is a single case experimental report, and can be considered a pilot study preceding a possible larger group study. We used this design because, to our knowledge, no study exists that has addressed the issue of the prevalence of neglect patients with a dissociation between near and far space neglect in walking. Since we cannot exclude that these patients have a low incidence, we wanted to assess whether PA would work on this specific patient. When single case research designs are employed, the patient undergoes different treatments in a pseudo-randomized order, and thus acts as his/her own control (Brossart et al., 2008; Bulté and Onghena, 2008).

The aim of the present study was to investigate the effect of PA on two different bisection tasks (bisection by reaching/pointing and bisection by walking) in a right brain-damaged patient (MR) with a dissociation between near and far space neglect. In particular, MR presented with more severe neglect in far than in near space in both bisection tasks. The dissociation was stronger in the bisection by reaching/pointing than in the bisection by walking task. It is worth noting that patient MR had left neglect in conventional cancelation and drawing tasks, but bisected line segments to the left of the objective midpoint (right neglect) both in conventional line bisection and in bisection by walking tasks.

Greater severity of far space neglect was especially evident if we consider the PBE, that is the error computed on the basis of the initial direction of the walking path (see Figure 7). However, MR partially corrected her initial walking error as she approached near space, as evidenced by the significant reduction of the bisection errors when she reached the line (OBE). This walking pattern shows that patient MR updated space representation during walking according to the degree of severity of her neglect in far vs. near space. It is very likely that MR activated the most impaired representation at the beginning of each walking path in far space and the less impaired representation while approaching the target in near space. According to our hypotheses, this indicates that the representation guiding MR’s line bisection is the last representation activated during walking, i.e., near space representation.

In patient MR we also evaluated the effect of PA in bisection by pointing and in bisection by walking tasks. In the pointing task the effect of PA was significant starting from session no. 4, where bisection error reduced to a value close to 0%. However, neglect reappeared in the follow-up session, which occurred 3 months after session 4. This indicates that, in the case of bisection by pointing, the positive effect of PA was not long-lasting. Conversely, in the bisection by walking task the effect of PA was maintained for a longer time. In particular the effect was still present 15 months after the last PA session. It is worth noting that PA primarily influenced the PBE parameter, that is the walking direction estimated at the beginning of the walking path, while the trajectory curvature per se did not change (see Figure 11): this is evidenced by the fact that the difference between PBE and OBE prior and after PA did not significantly change. According to our hypothesis, the reduction of PBE by PA strongly suggests the restoring of the more compromised representation, i.e., far space representation, before gait execution. This indicates that PA has a central effect on spatial representation, directly affecting higher level components of space representation rather than influencing lower level on-line recalibration factors. Importantly, this conclusion is confirmed by the fact that PA was carried out with prismatic lenses oriented so as to deviate MR’s visual field toward the right space (as it is normally done in order to reduce neglect for the left side of space), despite the fact that MR showed apparent neglect for the right side of space in line bisection tasks (MR misbisected segments to the left of the objective midpoint in both bisection by reaching/pointing and in bisection by walking). Because in conventional copying and cancelation tests patient MR showed left side neglect, we reasoned that MR’s leftward deviation was likely to be the consequence of compensatory strategies, a sort of leftward motor hyper correction, rather than a genuine right side neglect. Indeed, a similar behavior is known to be displayed by neglect patients that might compensate for their exogenous orienting deficit and ipsilesional deviation of the subjective midline by means of relatively intact endogenous searching processes (Bartolomeo and Chokron, 2002; Huitema et al., 2006). Therefore, we used right deviating prism to be sure that we did not change the usual rehabilitation procedure employed for left side neglect patients. The rationale was that if prism adaptation acted on on-line recalibration factors, we should have found a further deviation toward the left of the patient’s walking trajectory (i.e., a worsening of bisection performance). Instead, we observed a rightward deviation that showed an improvement of neglect. This means that the effect of PA intervenes before actual walking initiation, presumably on the higher spatial representation levels preceding movement execution and known to be affected in neglect.

It is unlikely that the observed results are influenced by fatigue effects. Despite the long duration of each experimental session (approximately 2 h), the patient’s performance did not decrease with time. Indeed, if this was the case, a worse performance should be expected toward the end of the experiment. This did not happen: immediately after PA-applied during the second half of the experimental session – neglect ameliorated, as shown by the reduction of bisection errors.

A novel finding of our research is that PA obtained through manual pointing (requiring visuo-motor coordination of the upper limb) transfers to gait (requiring motor coordination of the lower limbs). In line with our results, Tilikete et al. (2001) showed that PA can extend to body regions different from the one which has been adapted and that a brief adaptation to rightward shifting prisms in a reaching task generalizes to the postural system and improves neglect patient’s postural imbalance. More recently, Savin and Morton (2008) showed that arm pointing adaptation generalizes to leg pointing (see also Morton and Bastian, 2003, for somehow different results: the authors found that PA during walking generalized to reaching, but adaptation during reaching did not generalize to walking. It is worth noting that one factor that could account for the difference between these findings and ours is that Morton and Bastian tested normal subjects: it is well known that the effect of PA on normal subjects is limited if compared with the effect on neglect patients (Colent et al., 2000; Michel et al., 2003a,b). Furthermore, direct comparison of our single case experimental results with those from small group studies should be considered with caution given the difference in the two experimental designs.

Our findings may have important implications for the rehabilitation of neglect patients. Neglect symptoms may, at least partially, spontaneously recover in the acute phase post stroke (see Farnè et al., 2004), but only a very small percentage of patients (9% in the study by Farné et al.) show a complete remission of all symptoms (Hier et al., 1983; Samuelsson et al., 1997; Katz et al., 1999). Among the symptoms that may become chronic are gait deficits that prevent neglect patients to navigate safely through the environment. Symptomatology can vary from frequent falls (Webster et al., 1995) and bumping into objects located in left space (Grossi et al., 2001) to generic locomotion problems in daily living transfer activities (Nijboer et al., 2013) and a deviated walking trajectory (Brain, 1941; Berti et al., 2002; Huitema et al., 2006).

The efforts to rehabilitate unilateral neglect are further complicated by the presence of anosognosia (Halligan and Marshall, 1998), leading to a scarce cooperation of the patient in the rehabilitation programs. As a result, the presence of neglect after stroke remains one of the major factors associated with a poor functional outcome (Denes et al., 1982; Edmans et al., 1991; Jehkonen et al., 2000). Not surprisingly, a large variety of different rehabilitation techniques have been developed in order to treat neglect (see Luauté et al., 2006 for a review). PA has demonstrated to be one of the most effective. Among the symptoms showing improvement following PA are the following: the deficit of exploration of contralesional visual-space (Ferber et al., 2003), contralesional somatosensory perception (McIntosh et al., 2002; Maravita et al., 2003; Dijkerman et al., 2004), wheel-chair navigation (Jacquin-Courtois et al., 2008), and postural imbalance (Tilikete et al., 2001; Michel et al., 2003b). To the best of our knowledge PA has never been used to correct the deviated walking trajectories of neglect patients, except for a study by Keane et al. (2006) in which two ambulatory patients were shown to improve their walking abilities after PA. However, patients in this study were simply required to walk through a hallway and the authors only reported that their walking path, directed toward the right half of the hallway prior to PA, occupied the middle of it following PA. It is therefore unclear to what extent walking profited from PA and if prisms acted at the level of gait representation, gait execution, or both. Our results show that PA acts more upon the spatial representation activated at the beginning of the walking path (when the direction of the walking trajectory is first computed) than on the modulation of spatial representation during gait execution. This result may be specific for our patient, in which the far space representation – activated at the beginning of walking – was significantly more compromised than the near space representation – activated only successively, at some point during the patient’s approach to the target. Therefore, it is not surprising that the effect of PA, in this case, is stronger on the far than on the near space representation.

A further interesting and promising characteristic of PA is the long-lasting duration of its beneficial effect upon spatial representation of gait trajectory. In our case, four sessions of PA were sufficient to produce a positive outcome which lasted up to 15 months after treatment (the duration of the effect of PA on the bisection error by reaching was smaller: 3 months after treatment the bisection error reappeared). Indeed, long-lasting effects of PA after repeated and prolonged sessions of treatment have been demonstrated in previous works. In a study by Frassinetti et al. (2002) seven neglect patients were treated with two sessions of PA per day for 2 weeks and six out of seven showed an improvement of the symptomatology, in a standardized battery of visuo-spatial tests, that was maintained up to 5 weeks after treatment. In a more recent study by Serino et al. (2007), 16 neglect patients were submitted to a PA treatment for 10 daily sessions over a period of 2 weeks and showed ameliorated visuo-spatial abilities up to 3 months after treatment. Rusconi and Carelli (2012) have shown an amelioration of neglect in seven patients after 2 weeks of treatment with PA that was maintained up to 30 months after the end of treatment. In our study, four sessions of PA distanced in time one from the other, have determined a long-lasting amelioration in MR’s neglect walking trajectory. One could argue that her improvement could alternatively be attributed to spontaneous recovery. However, as we assessed MR’s neglect 10 months after stroke, this is unlikely to be the case: it has been demonstrated that neglect symptoms tend to improve up to 6–9 months from lesion, and stabilize or get worse after such time interval (Cherney and Halper, 2001).

An interesting aspect of PA in our patient is that its positive effects increase over time: both in manual and in walking bisection tasks, pre-adaptation bisection errors in the last PA session (session 4: 67 days apart from session 1) are significantly smaller than pre-adaptation errors in the preceding PA sessions (see Figures 9 and 12) (see Fortis et al., 2010, for a similar result). Additionally, the improvement in the walking trajectory is maintained 15 month after treatment, longer than the improvement in the bisection by pointing task (McIntosh et al., 2002; Pisella et al., 2002). These results should not surprise us if we consider the important role of the cerebellum in walking and in PA. On the one hand, it is well known that cerebellar lesions can produce a gait deficit known as cerebellar gait ataxia and that the cerebellum participates in postural balance (Tilikete et al., 2001), locomotion balance and, to a lesser degree, in leg coordination (Morton and Bastian, 2003); on the other hand, lesions of the right cerebellum impair adaptation to right-shifting prisms (Pisella et al., 2005) and cerebellar activation during PA in neglect patients covariates positively with the left spatial neglect improvement (Luauté et al., 2006). Hence, the cerebellum is a good candidate to play an important role in mediating the long term improvement of walking trajectory induced by PA in our patient (indeed, MR’s lesion spared the cerebellum). To investigate this possibility, fMRI research should examine the long-term plastic changes in the cerebellum in response to PA in neglect patients with gait deficits.

An alternative (or additional) explanation of the difference in the duration of the improvement induced by PA in the two bisection tasks calls into play the role of the dorsal stream in visuo-spatial processes. Specifically, according to recent anatomical and functional animal and human data (Kravitz et al., 2011), the dorsal stream gives rise to three distinct pathways: a parieto-prefrontal pathway, a parieto-premotor pathway and a parieto-medial temporal pathway, each supporting different visuo-spatial functions. The parieto-medial temporal pathway, the retrosplenial cortex in particular, seems to be implicated in spatial-navigation. Interestingly, the retrosplenial cortex and the medial occipital-parietal cortex, which sends feedback signals to the former, are spared by the lesion in our patient; instead, the involvement of the temporal pole may have more severely affected spatial representation processes not specifically related to spatial-navigation ability, such as those implicated in the bisection by pointing task. This may be one reason why the effect of PA was more durable in the bisection by walking than in the bisection by pointing task.

In conclusion, our results show, for the first time, a long-lasting rehabilitative effect of PA on walking trajectory in a patient with chronic neglect: as few as four sessions of PA ameliorated neglect during walking for as long as 15 months post treatment. Following PA, far space neglect was reduced in our patient, allowing a better representation of gait trajectory right from the first step. Instead, the curvature of the walking trajectory did not change following PA, suggesting that PA did not influence the low level processes subserving gait execution. These results show that PA acts on high level spatial cognition rather than on peripheral sensory-motor processing and is responsible for the realignment of the egocentric frame of reference guiding our patient’s gait trajectory following treatment (Fortis et al., 2010). The results of our single case experiment support a future group study on neglect patients aimed at verifying whether PA can be employed as a long-lasting rehabilitative tool in neglect patients in which gait trajectory is deviated and are prone to the adaptation effect with prismatic goggles. Finally, we hypothesize that the cerebellum and/or the retrosplenial cortex could play a crucial role in mediating the long-lasting rehabilitative effects of PA on gait trajectory in our patient.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.