Cerebral Cortex V

Cerebral Cortex V 14 N 10 © Oxford University Press 2004; all rights reserved Cerebral Cortex October 2004;14:1164–1172; doi:10.1093/cercor/bhh076

The Anatomy of Spatial Neglect based on Voxelwise Statistical Analysis: A Study of 140 Patients

Hans-Otto Karnath1, Monika Fruhmann Berger1, Wilhelm Küker2 and Chris Rorden3

1Center of Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany, 2Department of Neuroradiology, University of Tübingen, Tübingen, Germany and 3School of Psychology, University of Nottingham, Nottingham, UK

A major challenge for any anatomical study of spatial neglect in neurological patients is that human lesions vary tremendously in extent and location between individuals. Approaches to this problem used in previous studies were to focus on subgroups of patients that are more homogeneous either with respect to the branch territory affected by the stroke or with respect to existing additional neuro- logical symptoms (e.g. additional visual field defects). It could be argued that such strategies might bias the conclusions on the critical substrate associated with spatial neglect. The present study thus addressed the high variability inherent in naturally occurring lesions by using an unselected, but very large sample size and by comparing a neglect group with a non-neglect group using voxelwise statistical testing. We investigated an unselected 7 year sample of 140 consecutively admitted patients with right hemisphere strokes. Seventy-eight had spatial neglect, 62 did not show the disorder. The incidence of visual field defects was comparable in both groups. For assessing lesion location, in a first step, we used conventional lesion density plots together with subtraction analysis. Moreover, due to the large size of the sample voxelwise statistical testing was possible to objectively estimate which brain regions are more frequently compromised in neglect patients relative to patients without neglect. The results demonstrate that the right superior temporal cortex, the insula and subcortically putamen and caudate nucleus are the neural structures damaged significantly more often in patients with spatial neglect.

Keywords: attention, brain-damage, human, orientation, parietal lobe, space, temporal lobe

Introduction Spatial neglect is a common and debilitating consequence of unilateral right-hemisphere brain damage. Patients with neglect fail to respond or orient to stimuli appearing in contra- lesional space. Neglect can lead to profound deficits in everyday behavior (e.g. eating, reading, navigating and grooming) and has also been shown to be predictive of a poor prognosis (Karnath and Zihl, 2003). Understanding the anatomical substrate of this deficit is therefore not only of theoretical but also of great clinical importance.

Heilman et al. (1983) conducted the first study designed to identify the cortical correlate of spatial neglect using modern imaging techniques. They analyzed the computerized tomog- raphy (CT) scans of 10 patients with spatial neglect and revealed an overlap of lesion location in the inferior parietal lobule and the temporo-parietal-occipital (TPO) junction. Three years later, Vallar and Perani (1986) also analyzed CT scans of right hemispheric stroke patients with spatial neglect. Sixteen neglect patients showed an overlap area involving peri- sylvian regions. In six patients, the brain lesions centered on

the parieto-occipital junction and in eight patients the overlap was found on the supramarginal gyrus of the inferior parietal lobule. Subsequent studies have largely confirmed these early findings, but have found additional pathology leading to spatial neglect (Perenin, 1997; Samuelsson et al., 1997; Leibovitch et al., 1998, 1999).

These early anatomical studies combined lesions from neglect patients regardless of their other symptoms. One potential confound was the inclusion of neglect patients with primary visual field defects (VFDs). Although field cuts and hemispatial neglect co-occur, VFDs obviously represent a separate disorder and cannot be regarded as an integral part of the neglect syndrome. If VFDs have masqueraded as neglect in studies of neglect anatomy it is possible that the cortical regions previously thought to be the crucial locus for neglect are instead significantly associated with the VFDs. Therefore it is possible that studies that include a considerable number of patients with clear field cuts may necessarily be biased toward identifying posterior regions (near the primary visual cortex and underlying optic radiation).

Karnath et al. (2001) examined the cortical overlap in patients with middle cerebral artery infarcts who had ‘pure’ visual field defects, i.e. who had field cuts but no symptoms of neglect. Not surprisingly, these patients showed damage to the subcortical optic radiation. However, it was also found that these lesions typically extended to cortical areas in the inferior parietal lobule and the TPO junction (as these cortical regions lie above the subcortical optic radiation). Therefore, the regions classically associated with neglect have also been implicated with visual field defects. This finding lends support to the notion that previous studies might have confused the anatomical effects of visual field defects with spatial neglect.

To test this possibility directly, in a recent study we inten- tionally excluded patients with visual field cuts, aiming to isolate the anatomical regions involved with the core deficit of spatial neglect (Karnath et al., 2001). Unlike previous studies, we observed that the centre of lesion overlap covered the right superior temporal gyrus (Brodmann areas 22 and 42) suggesting that the superior temporal cortex rather than the inferior parietal lobule is the critical substrate for spatial neglect in humans. This conclusion is fundamentally different from the conclusions of previous studies and offers a new perspective regarding the function of intact superior temporal cortex.

However, it has been suggested that exclusion of patients with primary visual field defects may be a problematic experi- mental strategy that may lead to an inadvertent selection bias in favour of patients with more anterior damage (Husain and Rorden, 2003). To address this criticism, the present study followed an alternative strategy for lesion analysis based on an

Cerebral Cortex October 2004, V 14 N 10 1165

unselected patient sample. This method compares a group of consecutively admitted neglect patients (some who also exhibit VFDs) with a control group of brain damaged patients who have a similar incidence of VFDs.

A major challenge for any anatomical study of spatial neglect in neurological patients is that human lesions vary tremen- dously in extent and location between individuals. This high variability will reduce the power of any analysis. One approach to this problem is to focus exclusively on patients with small lesions, but this approach leads to a series of problems. First, such a selection reduces the number of patients — which itself reduces statistical power. Secondly, it biases the conclusions towards identifying smaller brain systems. Suppose that damage to either a large, or a small area of the brain leads to neglect. Either area may be just as important to the genesis of neglect, but selecting patients with small lesions could lead to the conclusion that only the smaller area was involved. More- over, there is the problem that many patients exist who also have small lesions at exactly the same location but do not show spatial neglect. Therefore, imposing such selection criteria (e.g. only including patients with small lesions) has intrinsic dangers. In the present study, we thus address the high variability inherent in naturally occurring lesions by using an unselected, but very large sample size and by comparing a neglect group with a non-neglect group using voxelwise statis- tical testing.

The study was based on an unselected sample of 140 stroke patients (with or without visual field defects) consecutively admitted to the Neurology Department in Tübingen within a period of 7 years. Of this group, 78 exhibited spatial neglect. Anatomical studies that simply superimpose lesions from neglect patients, may reflect vulnerability of certain regions to injury (e.g. due to the vasculature of these regions) rather than any direct involvement with spatial neglect. Thus, it is neces- sary to contrast directly the lesion sites of these patients with those of right-brain-damaged control patients who do not exhibit neglect but are comparable with respect to relevant other variables, e.g. the incidence of VFDs.