Left visual neglect is a frequent consequence of lesions in the right hemisphere, entailing a defective awareness of left-sided events. Lesions determining neglect often overlap on the temporo-parietal junction.1 2 Conflicting evidence, however, indicates lesions of more rostral parts of the superior temporal gyrus.3 4 Signs of neglect can also occur after lesions to the ventrolateral prefrontal cortex (VLPFC),5 the medial temporal lobe,2 the occipital lobe and the corpus callosum,6 or after damage to two major rostro-caudal brain pathways, the superior (SLF)7 8 and inferior (ILF)9 longitudinal fasciculi. Thus rather than damage to single cortical modules, dysfunction of large cortical networks10 11 can be the crucial antecedent of neglect.7 8 12^–14

Diffusion tensor imaging (DTI) tractography can be used to track the long range white matter pathways15 and then explore, in a standardised brain space, their relationships with the lesions found in stroke patients with standard anatomical MRI. A recent meta-analysis13 of previous lesion overlapping studies demonstrated that the subcortical lesions of neglect patients invariably overlapped at or near the SLF. Disconnection between cortical modules might thus be a general mechanism of neglect.12 This possibility is also consistent with the results of monkey studies,16 17 rodent studies18 and computer simulations of attention.19

Here we describe four patients with strokes in the right hemisphere, two of whom showed signs of extrapersonal neglect on pencil and paper tests. We used DTI tractography to directly visualise the SLF, ILF and the inferior fronto-occipital fasciculus (IFOF), a pathway running the depth of the temporal lobe, not hitherto associated with neglect.

METHODS

Four right-handed patients with right hemispheric vascular stroke gave written informed consent to participate in the study, which was approved by the ethics committee of the Hôtel-Dieu Hospital, Paris, France. Patients performed a battery of pencil and paper tests, including tests of line bisection, target cancellation, identification of overlapping figures and copy of a landscape drawing (see table 1 and also supplementary material online for demographic and clinical data). MRI data were acquired using echo planar imaging at 1.5 T and DTI was acquired using 36 independent directions (full details of the MRI and DTI acquisition and processing are available in the supplementary material available online). Fibre tracking of the SLF, ILF and IFOF was performed with Brainvisa 3.0.2 (http://brainvisa.info/), using a two regions of interest approach.20 The reconstructed tracts were displayed in three dimension and the number of streamlines (a surrogate marker of tract volume) was counted for each fasciculus in both hemispheres (see supplementary material online).

RESULTS

Case Nos 1 and 2 demonstrated no signs of neglect on pencil and paper tests; case Nos 3 and 4 had signs of left neglect in more than three tests of the neglect battery (table 1). Figure 1 displays three dimensional reconstructions of the lesions and DTI tractography (see also supplementary material online).

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Figure 1 Three dimensional anatomical reconstruction of the patients’ lesions and lateral views (R, right hemisphere; L, left hemisphere) of the diffusion tensor imaging tractography of the superior longitudinal fasciculus (in green), the inferior longitudinal fasciculus (in blue) and the inferior fronto-occipital fasciculus (in red) for the four patients studied. For each hemisphere, the three fasciculi are displayed on a T1 sagittal native MRI slice in the anterior/posterior commissure referential.

Case No 1 displayed no signs of extinction or neglect on neuropsychological testing 9 days after the onset of an ischaemic stroke affecting both the inferior parietal and the superior temporal cortices, both of which have been considered as the crucial lesional correlate of neglect.1 4 Tractography reconstruction visualised bilaterally the intact SLF, IFOF and ILF.

Similarly, case No 2 had no signs of extinction or neglect when assessed 5 days after clinical onset. The lesion involved the posterior part of the insula, the whole temporal pole and the superior, middle and inferior temporal gyri, including the temporo-parietal junction. Subcortical white matter was also affected, but long range association tracts (SLF, IFOF and ILF) were intact.

Case No 3 had left visual and tactile extinction and signs of severe left neglect with anosognosia. The lesion involved the subinsular and temporal stem white matter, the body of the caudate nucleus, the lenticular nucleus, the middle part of the corona radiata and the inferior parietal lobe with the underlying white matter. Tractography reconstruction showed intact ILF and SLF in both hemispheres, and complete absence of the right IFOF. At follow-up testing, 34 and 41 days after clinical onset, case No 3 still showed signs of left neglect (see supplementary material online).

Case No 4 had a right haemorrhagic occipital–parietal stroke. Two years after onset, she still had left hemiparesis and signs of left neglect. The lesion involved the inferior and superior parietal lobe with underlying white matter, the cuneus and precuneus, the middle temporo-occipital gyrus and the posterior part of the inferior temporal gyrus. The tractography reconstruction showed intact ILF and SLF and complete absence of the right IFOF.

Neither patient No 1 nor 2 presented language deficits after stroke, which renders unlikely the possibility of them having an unusual pattern of hemispheric lateralisation.

The two regions of interest approach to tractography dissections allows the dissection of long range pathways, but it may underestimate the involvement of more superficial (U-shaped) fronto-parietal connections. Hence we have overlapped the lesions of the four patients to probabilistic maps of fronto-parietal connections, as derived from a normative dataset (see supplementary fig 2 online). This analysis showed that in all four subjects the lesions extended into superficial fronto-parietal connections, sparing deep long range SLF fibres.

DISCUSSION

We used DTI tractography to show direct evidence of disconnection of the major rostro-caudal white matter pathways in neglect patients with vascular lesions. Previous studies demonstrating white matter disconnection in patients with neglect relied on anatomical7 9 23 or functional14 MRI, and inferred the localisation of tract lesions either from general anatomical knowledge7 or from DTI in normal subjects.9 Compared with previous attempts, the use of DTI tractography allowed us to identify more precisely the white matter pathways that were damaged in neglect patients.

The present results suggest that (1) complete damage of the IFOF can be associated with chronic visual neglect and (2) cortical lesions sparing the SLF and IFOF, but damaging at least part of the IPL and superior temporal gyrus, two areas previously indicated as the critical cortical loci for spatial awareness,1 4 24 do not necessarily cause chronic visual neglect.

The limited number of subjects in this study does not allow us to generalise from these preliminary findings to all patients with neglect; nevertheless, they do suggest that the neuroanatomical correlates of neglect may be more complex than previously thought and highlight important hypotheses on the role of direct connections between occipital and frontal lobes in spatial processing.

The involvement of the IFOF in left neglect has not been described previously. The IFOF connects the VLPFC and medial orbitofrontal cortex to the occipital lobe20 and represents the only direct connection between the occipital and frontal lobes in humans.15 The inferior–lateral portion of the frontal lobe, a cortical end station of the IFOF, has been frequently associated with frontal neglect.25 Lesions to the occipital origin of the IFOF have also been described in left neglect.6 9 Finally, as the central part of the IFOF runs in the stem of the temporal lobe, it is possible to hypothesise an occipito-frontal disconnecting mechanism in those neglect patients with large lesions of the temporal lobe.4 24 It remains to be seen whether a lesion of the IFOF per se is sufficient to cause neglect, without involvement of other cortical and subcortical regions. In our patients, the inferior parietal cortex and the underlying U-shaped fibres were affected, which is in keeping with previous evidence from monkey studies16 and human patients.7 8 13 However, extension into the deep white matter of the parietal lobes is a factor that has not been considered previously and future studies in larger series should clarify the relationship between clinical manifestations of neglect and extension of white matter lesions to fronto-parietal connections.

Interestingly, we observed that the two patients with an IFOF lesion showed little asymmetry of performance on the line cancellation test (ie, a test without distracters), whereas they omitted most contralateral targets on the bells and letter cancellation tests. In the latter tests, a target/distracter discrimination is required, an additional factor that neglect patients with predominantly a frontal lesion seem to find particularly difficult.5 IFOF disconnection may deafferent the ventral frontal cortex from more posterior sources of visual input related, for example, to object identification. In the monkey, neuron populations in the lateral prefrontal cortex respond both to the location and identity of previously presented visual objects, thus allowing the integration of “what” and “where” information.26 Regions in the human VLPFC, which constitute a projection site for the IFOF, show lateral selectivity in the short time retention of spatial information27 and may be important in resolving perceptual ambiguity.28 Damage to these regions in the right hemisphere may bias towards the right the mental reconstruction of a number line.29 Furthermore, the right VLPFC is a cortical end point of the ventral spatial attentional network, which is important for the response to previously unattended targets, and whose dysfunction leads to neglect behaviour.14 The right VLPFC may represent a convergence zone of three streams of visual processing: (1) the occipito-temporal stream, dedicated to object processing,30 31 through the IFOF and the uncinate fasciculus,20 (2) the ventral parieto-frontal attentional network,14 presumably connected by the human homologue of the third branch of the SLF (described in the monkey by Schmahmann and Pandya32) and (3) the dorsal parieto-frontal attentional network,14 linked by the human homologue of the second branch of the SLF.8 32

In conclusion, these preliminary findings suggest that neglect is a syndrome with a heterogeneous clinical presentation and complex anatomical correlates, where damage to fronto-parietal and possibly occipito-frontal connections may impair visuo-spatial processing at different levels.