In the present study, we report detailed behavioral and anatomical findings in three patients with right-sided neglect after left hemisphere strokes. Two of the patients had predominantly left parietal damage, the third had lesions involving the frontal cortex. Despite this heterogeneity in cortical loci of lesions, white matter tractography demonstrated signs of fronto-parietal SLF disconnection in the left hemisphere of all the patients. This finding suggests an important role of left fronto-parietal dysfunction in right-side neglect, and complements analogous evidence for right SLF II-III disconnection in left neglect (Bartolomeo, Thiebaut de Schotten, & Chica, 2012; Bartolomeo, Thiebaut de Schotten, & Doricchi, 2007; Doricchi, Thiebaut de Schotten, Tomaiuolo, & Bartolomeo, 2008; Migliaccio, Agosta, Scola, et al., 2012; Migliaccio, Agosta, Toba, et al., 2012; Thiebaut de Schotten et al., 2008; Thiebaut de Schotten et al., 2014; Thiebaut de Schotten et al., 2005; Toba, Migliaccio, et al., 2018; Toba et al., 2017; Urbanski et al., 2011).
Behavioural results
The three patients analysed in the study presented with right neglect signs in paper-and-pencil drawing and visual search tests in the acute stage of the stroke and at three months post onset. After rehabilitation, results obtained by the patients in the same paper-and-pencil tests only slightly changed. Indeed, a systematic study assessing 78 subacute left hemisphere stroke patients (Beis et al., 2004) observed that drawing and visual search tests were the most representative tests to assess right-side neglect (12.8% of the tested patients presented with neglect signs in bells test and 10.4% in landscape drawing). However, these tests were also the most representative in the case of left neglect patients, as observed by Azouvi et al. (2002). Moreover, in previous studies, the error patterns of patients after left hemisphere lesions were characterized by (1) target omissions to both left and right sides of the page, (2) fewer omissions of targets overall, comparing with patients with right hemisphere or bilateral lesions and (3) non-significant hemispatial asymmetry (Weintraub et al., 1996). Our patients also subscribed to this general right neglect error pattern, with omissions on both sides of the page in visual search tasks. However, in the landscape copy, two (P2 and P3) out of the three patients perfectly performed this task after rehabilitation. Furthermore, one patient (P1) presented with pathological line bisection that persisted also in the second evaluation. Previous studies showed that only 6.4% of the left brain-damaged patients had signs of neglect in this task (Beis, et al., 2004) and that biased line bisection in long lines (200 mm) was mainly correlated with posterior lesions (retrorolandic cortex, including parietal, but also temporal or occipital regions, or both). These data are in agreement with the lesion localization of our patient. However, an inconsistent pattern of errors in line bisection should be noted for this patient in the second clinical assessment, where we observed deviations towards either the right or the left in the version proposed by D'Erme et al. (1987).
Additionally, only the patient P1 made one right-sided omission in the overlapping figures test in the second evaluation (at three months), this test being perfectly completed at the first evaluation (and perfectly completed by the other patients). Performance of right neglect patients on the overlapping figures test can be variable, being one of the reasons for which right and left neglect are considered as having (at least in part) different natures and underlying mechanisms (Beis et al., 2004; Gainotti, D'Erme, Monteleone, & Silveri, 1986). The overlapping figures were designed to test the focusing of attention on a relatively small display situated in the central vision. This is in contrast with tests requiring the exploration of larger displays, which are more likely to induce right-sided omissions in left brain-damaged patients (Gainotti et al., 1986). In the original study, when neglect was assessed on the basis of the contralateral extrapersonal space exploration, 41% of the right and 37% of the left brain-damaged patients in the explored population had pathological performance. When the capacity to focus attention in the central vision (as assessed with the overlapping figures) was tested, a significant difference was observed, 36% of the left and only 11% of the right brain-damaged patients from the same population (Gainotti, et al., 1986) performing pathologically.
Anatomical results
Results obtained in this study emphasize the role of the left SLF disconnection in right neglect in three patients presenting focal parietal and frontal strokes in the left hemisphere. Early studies on right neglect suggested that it would be preferentially associated with anterior lesions (Ogden, 1985). Beis et al. (2004) found evidence against this hypothesis, because in their sample pathological performance in line bisection, gaze deviation, anosognosia for visual and motor impairment and personal neglect correlated with left posterior lesions (retrorolandic cortex, including parietal, temporal and occipital regions). Other studies considered the possibility that right neglect would be the result of lesions situated in one or more left hemisphere regions, analogous to those areas producing neglect in the right hemisphere and constituting parts of a proposed neuroanatomical network for the spatial distribution of attention (posterior parietal cortex, frontal eye field, cingulate areas, thalamus, caudate, as well as their interconnections) (Mesulam, 1981, 1990). Our results agree with previous studies in confirming this hypothesis (Beume et al., 2017; Beume et al., 2020; Malherbe et al., 2018)see, however (Moore et al., 2021). Generally, severe right neglect was documented to be present in patients with bilateral lesions situated in parietal, occipital and temporal regions, but also in the basal ganglia and the thalamus, the larger of the two lesions being situated in the left hemisphere, posterior to the central sulcus (Bartolomeo et al., 1998; Weintraub et al., 1996). Among the three patients studied here, P2 had low FA values of the SLF in both hemispheres, suggesting possible dysfunction of the right hemisphere SLF networks. Patient P3 presented lacunes in the corpus callosum with a possible impact on the transfer of the information relevant for visuospatial attention among the two hemispheres. Inter-hemispheric disconnection, which may play a role in the chronic persistence of left neglect (Bartolomeo, 2019, 2021; Lunven et al., 2019; Lunven et al., 2015), might also contribute to lack of compensation from the healthy hemisphere (Bartolomeo & Thiebaut de Schotten, 2016) in cases of right-sided neglect. Patient P1 presented cortico-subcortical atrophy in both hemispheres, which may also suggest concomitant right hemisphere dysfunction. Further data is needed in order to confirm the hypothesis of the necessity of bilateral lesions in severe right neglect.
Implication for attentional models
Given that left neglect is more frequent, persistent and severe than right neglect after unilateral lesions, many theories attributed a dominant role to the right hemisphere for the control of spatial distribution of attention (Heilman, Watson, & Valenstein, 1993; Mesulam, 1999). These models postulate that the right hemisphere directs attention to both ipsilateral and contralateral hemispaces, whereas the left hemisphere is shifting attention only to the right hemispace. Thus, a single lesion in the right hemisphere gives rise to severe neglect because the intact left hemisphere does not have a role in the symmetrical deployment of attention, but only in directing attention to the right. A left hemisphere lesion could produce right neglect, but this would be compensated by the symmetrical distribution of attention controlled by the right hemisphere. Later, Corbetta and Shulman (2002) described (1) an attentional ventral system largely lateralized in the right hemisphere, specialized in the detection of behaviorally relevant stimuli, and (2) an attentional dorsal system distributed bilaterally involved in preparing and applying goal-directed behavior. The two systems are in permanent interaction in normal brains and both would be disturbed in neglect. That is, in these distributed large-scale networks, the left hemisphere correct functioning would also be essential in the deployment of spatial attention. This assumption has also been proposed in one of the earliest models of spatial attention (Kinsbourne, 1977) and confirmed in later studies conducted on left neglect patients (Corbetta, Kincade, Lewis, Snyder, & Sapir, 2005) that demonstrated during an fMRI paradigm, abnormal activations in structurally intact left hemisphere areas. Thus, the rightward spatial bias of acute neglect patients was associated with hyperactivity in the left dorsal parietal cortex, which normalized in the chronic stage and was accompanied by the behavioral recovery. A support of this model of hemispheric imbalance is given by a previous study (Vuilleumier, Hester, Assal, & Regli, 1996) that reported spatial neglect (as a result of a right hemisphere stroke) recovery after a second (left hemisphere) stroke (Toba, Godefroy, et al., 2020; Toba, Malherbe, et al., 2020; Toba, Zavaglia, et al., 2020; Valero-Cabré, Toba, Hilgetag, & Rushmore, 2020). The patients presenting neglect after left hemisphere lesions presented in the current study challenge these models and demonstrate, based on an in vivo reconstruction of white matter bundles, in agreement with functional MRI studies (Corbetta et al., 2005), that left hemisphere also has an important role in the distribution of spatial attention. Alternatively, or in addition, some degree of dysfunction in the right hemisphere SLF III network might be necessary for signs of right-side neglect to emerge (Bartolomeo & Seidel Malkinson, 2019).