Neurobiology of Unilateral Spatial Neglect - Semantic Scholar

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Neurobiology of Unilateral Spatial Neglect ARGYE E. HILLIS Departments of Neurology and Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, and Department of Cognitive Science, Johns Hopkins University, Baltimore, MD

Hemispatial neglect is a common and disabling consequence of stroke. Earlier studies aimed to identify a single area of the brain where damage caused neglect and sought a single disrupted process that could account for the symptoms. Recent studies have shifted toward identifying component processes and representations underlying spatial attention required for various tasks and identifying areas of the brain responsible for each component that together constitute the network of regions responsible for neglect. This review focuses on recent insights into the mechanisms of neglect, regions of neural dysfunction that cause disruption of particular components or forms of neglect, and potential means of ameliorating neglect. Converging evidence supporting these insights comes from new imaging modalities in acute stroke, functional imaging, transcranial magnetic stimulation, electrophysiological studies in humans, and single-cell recording studies in nonhuman primates. NEUROSCIENTIST 12(2):153–163, 2006. DOI: 10.1177/1073858405284257 KEY WORDS Hemispatial neglect, Spatial attention, Stroke recovery, Rehabilitation, Parietal lobe

A neurologist who meets a man whose face is shaved only on the right side, wearing a sweater with a sleeve only on the right arm, and eating food only off the right side of the plate will know instantly that the man has had focal damage to the right hemisphere, resulting in unilateral spatial neglect (USN). The syndrome of USN is among the most striking behavioral abnormalities caused by focal brain damage. It is not simply a loss of some function but a failure to detect or respond to stimuli specifically on the side of space contralateral to brain damage, while accurately detecting and responding to stimuli on the ipsilesional side. After right hemisphere stroke, USN can be manifest by failure to respond to pain on the left side of the body, brush one’s hair on the left, read the left side of the page or the initial letters of words, or respond to a voice coming from the left side, or even by denial that the left arm belongs to oneself. Although the phenomenon has fascinated neurologists, psychologists, and other neuroscientists for centuries, many important questions remain concerning the basic neural mechanisms responsible for USN. This article will review recent progress toward elucidating the neurobiology of neglect, particularly with respect to heterogeneous forms of USN, differences between USN caused by right versus left hemisphere lesions, modality-specific and modality-independent forms of USN, and recent advances in rehabilitation of USN. The research reported in this article was supported by NIH R01: NS047691. The author is grateful to Maurizio Corbetta for helpful comments on an earlier draft of this review. Address correspondence to: Argye E. Hillis, MD, MA, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Phipps 126, 600 North Wolfe Street, Baltimore, MD 21287 (e-mail: [email protected]).

Volume 12, Number 2, 2006 Copyright © 2006 Sage Publications ISSN 1073-8584

Heterogeniety of Unilateral Spatial Neglect It is widely agreed that USN is a heterogeneous disorder. Patients may neglect the left side of near space but not the left side of far space, or may neglect tactile information but not visual information on the left (see Vallar and others 2003). In addition, several investigators have distinguished between “attentional” or “visual-perceptual” neglect (failure to detect stimuli on the contralesional side) versus “intentional neglect” or “directional hypokinesia” (reduced movements toward the contralesional side of space) (Coslett and others 1990). Some authors have proposed that the frontal cortex is implicated in intentional neglect and the parietal cortex in attentional neglect (Mesulam 1981), but others have failed to find support for distinct lesion localizations for these different types of neglect (McGlinchey-Berroth and others 1996). Another framework that might explain these dissociations is the proposal that there are distinct pathways of visual (and perhaps other sensory input) processing—a dorsal stream for locating where a target is or how to respond to it and a ventral stream for object recognition. The dorsal stream may be specialized for spatial attention for guiding movements of the limbs toward targets (“intentional” aspects) and the ventral stream for recognizing targets (“attentional” aspects). Another classification of USN regards the spatial reference frame with which neglect is defined. For example, one might neglect the left side of space as defined by the viewer or the left side of each individual stimulus in one’s view. This classification is based on the hypothesis that object selection and recognition require computation of spatial representations with separate reference frames that are increasingly abstract (Marr 1982). This type of model can account for patterns of performance of brain-damaged patients (Caramazza and Hillis 1990;

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Behrmann and Plaut 2001). In our adaptation of such a model (Hillis and Caramazza 1990, 1991, 1995; Hillis and others 1998), the first level of representation is a viewer-centered representation; the spatial coordinates are those of the viewer’s visual field or peripersonal space. Although in Marr’s theory, this representation is two-dimensional, recent evidence suggests that even the initial, retinocentric representation is multidimensional (Edelman 2002). This viewer-centered level of representation is crucial for knowing where the object is and how to plan movements relevant to the object. Next, a stimulus-centered representation is computed in which the stimulus is represented as surfaces oriented with respect to the viewer; its location in the visual field is no longer represented. This level of representation specifies the orientation with respect to the viewer. Finally, an object-centered representation is computed in which the reference frame is defined by the object itself. In objectcentered representations, the orientation of the physical stimulus (e.g., backward or upside down) and its location with respect to the viewer are no longer represented. The left side of an object (e.g., the west side of a map) is always represented on the left side of an object-centered representation, even if the object is viewed upside down (e.g., such that the west side of the map is on the right of the stimulus/viewer). It is important to note that what we refer to as a “stimulus-centered” representation (a representation of a selected stimulus, with left and right defined by the viewer) is often referred to as “objectcentered” or “object-based” in the literature (Chatterjee 1994; Olson and Gettner 1995; Colby 1998). However, we have reserved the term “object-centered” to refer to viewer-independent representations of stimuli that have canonical orientations. In viewer-centered representations, the midline of the representation corresponds to the midline of the viewer’s visual field, head, or body. Evidence that USN can affect processing of the contralesional side (the side of space contralateral to the lesioned hemisphere) of a viewercentered representation comes from patients who make errors only on stimuli on the contralesional side of the viewer, irrespective of the orientation of the viewer or of the stimulus (Hillis and others 1998). Other studies have demonstrated an absence of viewer-centered USN in patients who have USN in other reference frames (Mennemeier and others 1994; Ota and others 2001). In stimulus-centered representations, the midline of the representation is defined by the midline of the stimulus and not the midline of the viewer. That is, the right and left are defined by the viewer’s right and left, but the absolute location of the stimulus relative to the viewer is irrelevant. To illustrate, if the word HORSE is presented to the viewer’s right side, the H is on the left side of the stimulus but on the right side of the viewer. Evidence for USN in this reference frame comes from patients whose errors increase as a function of the distance to the left of the stimulus but are not influenced by the position of the stimulus with respect to the viewer (Hillis and Caramazza 1991, 1995; Chatterjee 1994; Subbiah and Caramazza 2000). To demonstrate the dissociation

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between viewer-centered and stimulus-centered USN, Ota and others (2001) presented patients with USN a sheet of circles, of which half had gaps on the left or right side. Patients were instructed to circle stimuli without gaps and to cross out stimuli with gaps. One patient failed to mark stimuli on the left side of the page but correctly marked all stimuli on the right side of the page, including stimuli with left-sided gaps, indicating viewercentered USN. Another patient marked all stimuli on the page but incorrectly circled stimuli with left-sided gaps (failing to detect left gaps), consistent with stimuluscentered USN. In object-centered representations, the left is defined by the canonical orientation of the object, irrespective of the orientation or location of the object relative to the viewer. At this level of representation of the word HORSE, H always has the same relative position (to the “left” of the O), irrespective of whether the word is presented in standard print, mirror-reversed print, or spelled aloud. Evidence for USN at the level of object-centered representations comes from patients who fail to process one side of the canonical representation of objects with inherent left and right sides (e.g., words, letters, certain flags, or maps), even when the object is upside down or mirror-reversed (Baxter and Warrington 1983; Barbut and Gazzaniga 1987; Caramazza and Hillis 1990; Hillis and Caramazza 1990, 1995; Hillis, Newhart, Heidler, Marsh, and others 2005). Dissociations between viewer-centered, stimuluscentered, and object-centered USN have mostly been reported in small series or detailed studies of a few patients. In a relatively large study of neglect in different reference frames (95 patients), viewer-centered neglect was most common, followed by stimuluscentered neglect; object-centered neglect was least common (Hillis, Newhart, Heidler, Marsh, and others 2005; see also Hillis, Newhart, Heidler, Barker, and others 2005). These different patterns of USN are illustrated in Figure 1. Additional evidence that neural representations of space are encoded in different spatial reference frames comes from a variety of sources. Single-cell recording experiments in primates reveal that some neurons represent stimulus-centered coordinates of space. These neurons respond to eye movements directed to the left end of a bar, and not to movements in the same trajectory but directed to the right end of a bar (Olson and Gettner 1995). In contrast, other neurons have purely retinotopic (Duhamel and others 1997), or head-centered (e.g., Andersen and others 1985), response fields. In a recent review, Andersen and Buneo (2002) reported electrophysiological evidence that distributed populations of cells within the parietal cortex code auditory targets in head-centered coordinates; others code visual targets in eye-centered coordinates; others code touch in body-centered coordinates; and still others (the majority) represent stimuli in all input modalities in a common, eye-centered (view-centered) coordinate frame that is used to direct reaching or saccades.

Neurobiology of Unilateral Spatial Neglect

Fig. 1. Examples of errors reading sentences, words in standard print, and words in mirror-reversed print, with different patterns of errors that reflect distinct forms of unilateral spatial neglect (USN). Note that patients with all forms of neglect make errors on the contralesional side of single words in standard print. Viewer-centered USN and stimulus-centered USN can be distinguished by performance in reading sentences, with omissions of words on the contralesional side of the sentence in viewer-centered USN versus errors on the contralesional sides of individual words, throughout the sentences, in stimulus-centered USN. Stimulus-centered USN and object-centered USN can be distinguished by performance in reading mirror-reversed words, with errors on the contralesional side of the printed stimulus (the final letters) in stimulus-centered USN versus errors on the contralesional sides of the canonical representation of words (the initial letters), in object-centered USN.

Recent studies have also provided evidence that distinct neural regions are involved in computing spatial representations with different reference frames. Electrophysiological studies in primates provide data indicating that neurons in the posterior parietal cortex encode viewer-centered representations that guide spatial aspects of intention as well as attention (Colby and Goldberg 1999), whereas neurons in the temporal cortex are relatively indifferent to location and orientation of objects in space (Gross and others 1972; Sakata 2002). Cortical ablations and use of axonal transport of tracer substances in primates have also identified distinct spatial maps with different reference frames within intrahemispheric neuronal networks of spatial attention (Rizzolatti and others 1985; Rizzolatti and Gallese 1988). However, localization of spatial representations with different reference frames may differ in humans because in primates, left hemisphere lesions are as likely to cause USN as right hemisphere lesions. However, a number of authors have proposed that distinct regional components of a right hemisphere network of attention in humans have different roles in spatial processing (Mesulam 1981, 1999; Vallar and Perani 1985). Relatively few studies have investigated the neural substrates of spatial representations with separate refer-

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ence frames or in separate modalities in humans. It was previously difficult to localize lesions associated with different types of USN, in part, because of the large lesions associated with chronic USN, making it difficult to identify the part of the lesion responsible for residual deficits. Furthermore, patients show variable degrees of recovery and reorganization of structure/function relationships following stroke. Thus, even if an area of damage initially caused a particular type of USN, the form of USN may have recovered before the time when patients are studied, months or years after stroke. In acute stroke patients, it was previously difficult to determine the entire areas of neural dysfunction that might be responsible for the form of USN observed because areas of low blood flow surrounding the core infarct contribute to the deficits in acute stroke. However, recent advances in magnetic resonance imaging allow identification, within minutes or hours of stroke, of both areas of dense ischemia or infarct using diffusion weighted imaging (DWI) and areas of low blood flow using perfusion weighted imaging (PWI). This combination of scans reveals the entire region of tissue dysfunction responsible for the deficits. Taking advantage of these new imaging methods, a recent study of 50 patients with acute right subcortical stroke revealed that distinct areas of dysfunctional

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Fig. 2. Top panel, In two studies, viewer-centered unilateral spatial neglect (USN) in copying and the gap detection task (left and middle images) was strongly associated with hypoperfusion of the right angular gyrus and supramarginal gyrus (right image). Areas that are blue or dark green on the perfusion weighted imaging scans represent areas of significant hypoperfusion (delayed arrival of contrast). Bottom panel, In both studies, stimulus-centered USN (left and middle images) was strongly associated with hypoperfusion of the right superior temporal gyrus, as shown on the right.

cortex were associated with viewer-centered versus stimulus/object-centered neglect (Hillis, Newhart, Heidler, Barker, and others 2005). Patients underwent a battery of tests of USN, PWI, and DWI within 48 hours from onset of stroke to identify areas of tissue dysfunction that were associated with different types of neglect before substantial reorganization of structure/function relationships or development of compensatory strategies. The presence of left viewer-centered neglect was strongly associated with hypoperfusion of the right angular gyrus (Fisher exact: P < 0.0001), whereas presence of stimulus/object-centered neglect was strongly associated with hypoperfusion of the right superior temporal gyrus (STG) (P < 0.0001). Object-centered neglect was not distinguished from stimulus-centered neglect in this study. The location of the subcortical infarct did not contribute to either the presence or type of USN. In a separate study, 95 patients with acute nondominant hemisphere stroke were tested in reading words in various orientations to identify areas of neural dysfunction associated with neglect in each reference frame (Hillis, Newhart, Heidler, Marsh, and others 2005). As in the previous study using the same basic methodology (DWI, PWI, and tests of USN within 48 hours of stroke onset), various forms of neglect were associated with infarct and/or hypoperfusion in specific regions. In this study, similar localizations for viewer-centered neglect and stimulus/object-centered neglect were identified. Viewer-centered left neglect was associated with

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hypoperfusion and/or infarct of the right angular gyrus (χ2 = 23.2; df = 1; P < 0.0001), right supramarginal gyrus (χ2 = 12.0; df = 1; P < 0.0004), and right visual association cortex (χ2 = 43.5; df = 1; P < 0.0001), but not the right STG or posterior, inferior frontal gyrus. In contrast, stimulus-centered USN was associated with hypoperfusion and/or infarct of the STG (χ2 = 15.2; df = 1; P < 0.0001), and not with imaging abnormalities in the right posterior, inferior frontal gyrus, angular gyrus, supramarginal gyrus, or visual association cortex (Fig. 2). In this study, stimulus- and object-centered neglect were also distinguished. Object-centered neglect was observed only after left superior temporal dysfunction (on DWI and/or PWI) in left-handed patients. These findings are consistent with the influential proposal of Goodale and Milner (1992; see also Mishkin and others 1983) specifying a “dorsal stream” for visual, tactile, and motor exploration (for knowing where an object is or how to plan movements with respect to an object) involving the parietal lobe and a “ventral stream” for object recognition (knowing what the object is) involving the temporal lobe. Because these two processes require different types of spatial maps, it would be parsimonious if spatial maps with different reference frames are represented in separate cortical regions critical for each process (Strong 1994). Functional imaging studies have also provided evidence that dorsal parietal and associated frontal cortices (bilaterally, but mainly right hemisphere) are involved in egocentric or viewer-


centered spatial coding (Galati and others 2000; Committeri and others 2004), whereas the ventral occipitotemporal cortex is involved in object-centered attention (Arrington and others 2002; Committeri and others 2004). These results might account for conflicting findings regarding the lesions that produce USN. Most studies have reported left USN associated with lesions in the right parietal cortex or temporoparietal junction (Vallar 1998; Mort and others 2003), whereas recent studies have found that left USN is more strongly associated with right STG (Karnath 2001; Karnath and others 2004), or either right frontal or parietal regions (Mesulam 1981, 1999). These conflicting results may reflect different types of USN (with different reference frames), in that USN was tested in various ways across studies. Neglect after Left versus Right Hemisphere Lesions In humans, more frequent and severe USN is observed after right hemisphere lesions than after left hemisphere lesions, at least in right-handed individuals. This hemispheric difference is not detected in nonhuman primates or other animals. The hemispheric difference has been attributed to the dominance of language in the left hemisphere (of dextrals) in humans, such that the right hemisphere has become dominant for spatial representations or spatial attention. The hypotheses outlined below may apply to right-handed individuals only because hemispheric differences may be attenuated, reversed, or unchanged in left-handed individuals and because all of the relevant studies (unless otherwise stated) were conducted in dextrals only. There are competing hypotheses about the neural basis for the distinction between hemispheres with regard to the incidence and severity of neglect caused by focal lesions in each. One hypothesis is that neurons in the right frontal and parietal cortex represent or modulate attention to both sides of space, whereas neurons in the left frontal and parietal cortex represent or modulate attention to predominantly the right side (Heilman and Van Den Abell 1980; Mesulam 1981, 1999). In this theory, only a right hemisphere lesion will result in severe USN, when only the left hemisphere’s attention to the right side of space is preserved. After a left hemisphere lesion, the right hemisphere would be spared, with bilateral representations of space and attention to both sides (Fig. 3A) (Weintraub and others 1996; see Corbetta and others 1993 for evidence from PET). A related hypothesis is that within each hemisphere, there is a bias of attention toward the contralateral side, such that there is a gradient of USN (becoming worse further to the contralesional side; Kinsbourne 1977) but that the slope of the gradient is steeper in the left hemisphere (Fig. 3B) (Barton and others 1998). In this hypothesis, most cells in the left hemisphere regions responsible for attention have contralateral receptive fields; more cells in the homologous right hemisphere regions have bilateral receptive fields. The proportion of cells with contralat-


eral versus bilateral receptive fields could produce a gradient of spatial attention, steeper in the left hemisphere (Rizzolatti and others 1981; Pouget and Driver 2000). A third hypothesis is that there is a similar contralateral bias in spatial attention in each hemisphere (mediated by the intraparietal sulcus) but that the right STG and temporoparietal junction (TPJ) are specialized for nonspatial aspects of attention, including vigilance and reorienting attention to unattended locations (Fig. 3C) (Corbetta and others 2000; Corbetta and Shulman 2002; Shulman and others 2004). By this hypothesis, USN is most severe when a lesion involves both the dorsal parietal cortex spatial attentional bias and the right temporoparietal nonspatial attentional mechanisms that reorient attention to stimuli in unattended locations. Evidence for a gradient of spatial attentional mechanisms in each hemisphere, biased to the contralateral side, comes from a variety of sources. For instance, patients with USN show a gradient of errors, gradually increasing toward the contralesional side (Marshall and Halligan 1989; Butler and others 2004). This gradient of errors can be demonstrated in both peripersonal space and far extrapersonal space (Butler and others 2004). Evidence that there are distinct mechanisms for spatial attention (searching for a target across spatial locations, enhancing perception to a particular location with respect to the viewer) in the bilateral intraparietal sulcus, and mechanisms for reorienting to targets in unattended locations in the right temporoparietal cortex, comes from two main sources. First, functional imaging studies show distinct areas of activation during these aspects of attention. For example, fMRI studies of detection of a particular target in a spatial field reveal increased blood oxygen level dependent (BOLD) signal in the bilateral intraparietal sulcus prior to and during presentation of the target that increases when the target is presented (Corbetta and others 2000; see also Yantis and others 2002). This bilateral dorsal parietal mechanism may be considered a “top down” attentional mechanism for preparing for stimulus selection and goal-directed responses to particular locations (Corbetta and Shulman 2002). In addition, the same studies show increased BOLD in the right TPJ when the target appears and attention must be reoriented to an unattended location (see also Arrington and others 2002). This ventral right temporoparietal mechanism may be considered a “bottom-up” mechanism for stimulus detection (or convergence zone for bottom-up and top-down influences on attention), which is right hemisphere lateralized. Second, physiological studies employing single-cell recording in nonhuman primates demonstrate increased neural activity in the intraparietal sulcus and frontal cortex during the period before a target is presented in a particular contralateral location, indicating these areas are critical for attending to motivationally relevant space (Bushnell and others 1981; Bisley and Goldberg 2003). Recent data from patients with USN provide evidence for the following account of the greater incidence and severity of USN after right- than left-sided lesions, which combines the proposal of unequal attentional

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Fig. 3. A schematic representation of various accounts of the greater frequency and severity of unilateral spatial neglect (USN) after right relative to left hemisphere lesions in humans. Attention by the right hemisphere is shown in green; attention by the left hemisphere is shown in yellow. Darker shades represent greater attention. The top section (1) represents attention to the left and right of space in the absence of brain lesions. The left lower section (2) represents spatial attention after right hemisphere stroke (left neglect), and the lower right section (3) represents spatial attention after left hemisphere stroke (absent or mild right neglect). Panel A in each section represents the theory that the right hemisphere directs attention to both sides of space, whereas the left hemisphere directs attention to predominantly the right side. Panel B in each section represents the theory that within each hemisphere, there is a bias of attention toward the contralateral side, but the gradient of attention has a steeper slope in the left hemisphere. Panel C in each section represents the theory that there is a bias of “top-down” spatial attention toward the contralateral side by each hemisphere, but also right hemisphere specialization for reorienting of attention. Therefore, right hemisphere lesions would reduce nonspatial reorienting, shown as a higher threshold for detection (represented by the dashed line) after right hemisphere stroke, compared to the normal threshold for detection (represented by the solid line). The combination of unbalanced spatial attention to the right and raised threshold for detection (on both sides) would result in failure to detect stimuli on the left. In addition, the gradient of spatial attention in the undamaged hemisphere might be steeper (not shown) after a lesion in the opposite hemisphere because of the loss of inhibition by the lesioned hemisphere.

gradients across space with the proposal of a bilateral dorsal parietal top-down spatial attention mechanism and a right temporoparietal bottom-up stimulus detection mechanism. On this account, damage to either dorsal parietal cortex would cause errors on the contralesional side because the spatial attention mechanism of the other hemisphere would be responsible for enhancing perception of stimuli across space, biased toward the contralateral side. More specifically, after a lesion in the right intraparietal sulcus, the left top-down spatial attention mechanism will enhance perception stimuli on the right more than the left. However, frank USN would be unlikely as long as the right temporoparietal bottom-up

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reorienting mechanism is intact because this bottom-up mechanism would be used to reorient attention to stimuli on the left, supporting detection of most left-sided stimuli. However, if the right temporoparietal reorienting mechanism is also impaired, only the left dorsal parietal top-down spatial attention mechanism, biased to the right, would be available for perception, resulting in left severe USN—failure to detect or respond to stimuli on the left. The temporoparietal reorienting mechanism would essentially increase the threshold for stimulus detection across the spatial field, such that left-sided stimuli would be below the threshold for detection. This hypothesis would account for the greater frequency and


severity of USN after right than left hemisphere damage, in that only right hemisphere damage can disrupt both the dorsal parietal spatial attention mechanism and the right temporoparietal reorienting mechanism. This account would predict that strokes involving the left or right intraparietal sulcus would result in subtle contralesional USN because perception of ipsilesional stimuli would be enhanced. It would also predict that severe USN would be observed only after damage to both the right intraparietal sulcus and right temporoparietal cortex. Data from patients with USN are consistent with these predictions about detection of stimuli in locations across spatial locations with respect to the viewer. Several studies have demonstrated a gradient of errors, increasing toward the contralesional side, in patients with both right and left hemisphere damage, but with greater errors in stimulus detection after right hemisphere lesions (reviewed above). Furthermore, this linear increase in errors across the visual field appears to be most reliable in patients with parietal lesions. Additionally, several studies have reported more subtle spatial attention deficits after left compared to right hemisphere lesions. For instance, a study of 89 patients who were tested at an average of 10.8 weeks after left hemisphere stroke revealed right neglect as measured with drawing and line cancellation tasks (of the type shown in Fig. 1) in 10% to 13% of patients and right neglect on at least one test of neglect in 43.5% of patients (Beis and others 2004). On all tests, a lower percentage of patients with left hemisphere stroke showed neglect (error scores and/or right/left difference scores above the cutoff for normals), compared to patients with right hemisphere stroke who had been studied on the same battery of tests. However, in this study, 16.8% of patients were left-handed, and cutoff scores for “personal neglect” (delayed reaching for the contralesional arm) may have been influenced by impaired proprioception in the contralesional arm rather than neglect, so the incidence of right USN after left lesions may have been overestimated. Other studies have reported the frequency of right neglect, at variable times after stroke, ranged from 0.3% to 9% of patients (Hecaen 1962; Pedersen and others 1997). Nearly all studies report a lower frequency of USN after left than right hemisphere stroke. Furthermore, neglect is more severe after right than after left lesions. For instance, error rates in marking lines on the contralesional side in line cancellation tests are much higher after right than left hemisphere lesions (Ogden 1985). There is also evidence that damage to the right intraparietal sulcus and right TPJ is more likely to cause USN than damage only to the right TPJ. For example, a study of 74 patients studied within 24 hours of acute stroke on a battery of tests for USN, DWI, and PWI revealed a strong correlation between severity of USN and volume of dysfunctional tissue measured on PWI (Hillis and others 2003). If USN depended only on damage or dysfunction of one particular area of the brain, there would not likely be an effect of the volume of hypoperfusion. However, to more directly test this hypothesis,


we reexamined the scans of 50 patients in the previously described study in whom viewer-centered neglect was associated with right angular gyrus hypoperfusion and stimulus/object-centered neglect was associated with superior temporal hypoperfusion (Hillis, Newhart, Heidler, Barker, and others 2005). Because the intraparietal sulcus borders on the dorsal angular gyrus (and supramarginal gyrus) and the TPJ includes the ventral angular gyrus, we hypothesized that viewer-centered neglect in this study was associated with hypoperfusion of both the intraparietal sulcus and TPJ. The areas of the PWI scans were reanalyzed by a technician without knowledge of the hypothesis or the patients’ performance on USN tests. This reanalysis demonstrated that all but two patients with viewer-centered neglect showed hypoperfusion of both the intraparietal sulcus and the right TPJ. Furthermore, only one patient with hypoperfusion of both regions had no evidence of viewer-centered neglect. Therefore, dysfunction of the combined regions was highly associated with viewer-centered neglect (χ2 = 34.6; df = 1, P < 0.0001). In contrast, the combination of superior temporal and intraparietal sulcus hypoperfusion was not associated with stimulus/object-centered neglect, indicating that the temporal spatial bias alone (without concurrent deficits in vigilance or reorienting) may be sufficient to cause stimulus/object-centered neglect. The implication of this conclusion is that stimulus/objectcentered neglect may be equally common after right and left superior temporal lesions or that there are differences between hemispheres in the slopes of attentional gradients in stimulus- and object-centered reference frames. These possibilities require further study. Modality-Specific Neglect Many previous studies have reported dissociations between neglect in various modalities of input (De Renzi and others 1989; Bisiach and others 2004). There is some recent evidence that different cortical areas are critical for spatial attention and perception in different sensory modalities. For instance, a recent study of extinction in different sensory modalities revealed distinctions in the areas responsible for visual, tactile, and motor extinction with double simultaneous stimulation (Hillis and Chang 2004). In this study, 88 patients with right supratentorial ischemic stroke less than 24 hours from onset were imaged with DWI, PWI, and conventional MRI and were tested for visual extinction (detection of finger movement on the left, right, or bilateral visual fields to confrontation), tactile extinction (detection of tactile stimulation on the left, right, or bilateral limbs or face to confrontation), and motor extinction. Motor extinction was tested by asking patients with right ischemic stroke to “click” as many times as possible with the left hand, right hand, or both hands (once with arms crossed over the chest, once with arms uncrossed), as many times as possible in 1 minute. Visual extinction was most strongly associated with infarct and/or hypoperfusion (neural dysfunction) of the right visual association cor-

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tex (Brodmann area 19), tactile extinction was associated with infarct and/or hypoperfusion of the right inferior parietal lobule (angular gyrus and supramarginal gyrus), and motor extinction was associated with hypoperfusion of the right STG. Visual and tactile extinction frequently co-occurred, and the combination was most strongly associated with hypoperfusion of both the right visual association cortex and inferior parietal lobule. These results might reflect in part the distinctions between viewer-centered and stimulus/object-centered USN. That is, because visual and tactile extinction tests defined “left” as the left side of the viewer, it is not surprising that these forms of viewer-centered extinction were associated with infarct/hypoperfusion of the left angular gyrus and visual association cortex. Motor extinction was measured as extinction (discontinued use) of the contralesional hand prior to the ipsilesional hand in the clicking task, irrespective of the side of the viewer in which the hand was placed. That is, all but one patient with motor extinction extinguished the left (contralesional) hand whether it was on the left side of the body (uncrossed condition) or the right side of the body (crossed condition). This type of motor extinction might be considered a type of “object-centered” neglect, in the sense of one’s own body as an object (in which the left arm is represented on the left of the object, even if it is crossed over to the right side of the trunk). Interestingly, the one patient who extinguished either hand on the left (contralesional) side of the body did not have hypoperfusion of the STG. These results are also consistent with the hemispheric rivalry account of the neural mechanisms of extinction (Kinsbourne 1977), which has received recent support from functional imaging studies and repetitive transcranial magnetic stimulation (TMS) investigations. In this account, extinction arises because each hemisphere is biased to attend to, or responds to stimuli presented in, the contralateral side of personal, peripersonal, and extrapersonal space, but each hemisphere inhibits the other through transcollosal pathways. Thus, extinction can be explained by proposing that the undamaged hemisphere, when activated, suppresses the weaker, damaged one. Although the damaged hemisphere can detect a contralateral stimulus when presented alone, it cannot do so when suppressed by the normal hemisphere that becomes activated when bilateral stimuli are presented. Consistent with this proposal, a recent study demonstrated that neural activation of ventral visual areas (Brodmann areas 18 and 19) in response to a visual stimulus in the opposite visual field in normal subjects, observed with PET, decreased when a visual stimulus was presented simultaneously in the ipsilateral visual field (Fink and others 2000). This result can be explained by assuming that a right visual field stimulus (presented simultaneously with a left visual field stimulus) activates the left hemisphere, which then suppresses the right hemisphere’s response to the left visual field stimulus. In normal subjects, the diminished response to the left stimulus might be adequate to detect it, even in the presence of a simultaneous right stimulus. However, in subjects

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with already compromised right hemisphere function, this suppression of inhibition might raise the activation response to the left stimulus above threshold for detection in the simultaneous condition. Furthermore, several groups have demonstrated that rTMS inhibition of the posterior parietal cortex in normal subjects reduced their detection of contralateral targets whenever concurrent ipsilateral targets were presented (Pascual-Leone and others 1994; Hilgetag and others 2001). These studies also showed that rTMS inhibition of the parietal cortex enhanced detection of ipsilateral targets in the presence of bilateral stimuli. Likewise, another study demonstrated that rTMS suppression of the parietal cortex (but not frontal cortex) improved detection of ipsilateral tactile stimuli (Seyal and others 1995). Results of these studies can be explained by proposing that parietal rTMS both suppressed the targeted hemisphere (resulting in reduced detection of contralateral stimuli) and suppressed the normal inhibition of the opposite parietal cortex (resulting in enhanced detection of ipsilateral stimuli). An electrophysiological study of a patient with tactile extinction revealed some residual, but attenuated, somatosensory-evoked potentials in the damaged hemisphere in response to contralateral tactile stimuli presented alone, but no somatosensory-evoked potentials in that hemisphere with bilateral stimulus presentation (Eimer and others 2002). This result can also be explained by the hypothesis that the intact hemisphere, when activated by ipsilesional stimuli, inhibits the damaged hemisphere and leads to a loss of the residual somatosensory response to contralesional stimuli in that hemisphere during simultaneous bilateral stimulation. Rehabilitation of Neglect The presence of USN has long been considered a barrier to progress in rehabilitation, in part, because it is often associated with anosognosia and general attentional deficits. However, a variety of behavioral interventions can be useful in ameliorating neglect (see Chatterjee and Mennemier 1998, for review), at least in some cases. However, there has not been an intervention that has proven to be useful for reducing USN in randomized clinical trials. Nevertheless, recent experimental findings in three domains provide promise for advances in rehabilitation of neglect. Several studies of patients with left USN due to stroke have now demonstrated that a brief period of practice pointing toward midline visual targets that are optically displaced to the right by 10° or 15° using prisms results in improved symptoms of USN for hours or days after practice (Rossetti and others 1998; Frassinetti and others 2002; see Mattingley 2002; Redding and Wallace, in press, for reviews). In several reported patients with chronic USN, performance on tactile exploration also improved after prism adaptation (e.g., Maravita and others 2003). The aftereffects of prism adaptation (pointing further toward the left and closer to midline targets after prism adaptation, compared to baseline performance in which patients with USN point toward the right of mid-


line targets) are often markedly exaggerated, relative to the aftereffects of prism adaptation in normal subjects. In a thorough and insightful review of the mechanisms underlying prism adaptation, Redding and Wallace (in press) propose that USN results from a combination of deficits in two components of selecting a region of space for a particular task: 1) pathologically reduced size of the work space for the task (calibration dysfunction) and 2) shift to the right of the coordinates of an egocentric sensory-motor reference frame with inability to spontaneously realign the coordinates of task work-space. They argue that prism adaptation results in realignment (bringing part of the neglected hemispace into the task work-space) but does not directly improve calibration. The identified components of USN might be comparable to the two components of egocentric USN proposed by Corbetta and colleagues (Corbetta and Shulman 2002; Shulman and others 2004). That is, calibration dysfunction, which is a limitation of the attentional window that is not specific to one side, may result from damage to the right angular gyrus/TPJ. The shift of egocentric coordinates of the task work-space to the right may result from a rightward bias in spatial attention by the intact left intraparietal sulcus, released from inhibition by a lesion in the right intraparietal sulcus. That is, damage to the right intraparietal sulcus would cause the task work-space to be pathologically shifted to the right. In the absence of calibration dysfunction, performance might be normal because an increase in size of the task work-space would allow compensation. However, if both calibration and realignment are impaired, the patient would fail to respond to left-sided targets because they fall outside of the task work-space. This proposal would account for the finding that neural dysfunction in both the right intraparietal sulcus and angular gyrus/TPJ is required to cause egocentric neglect. This account leads to the prediction that prism adaptation would not ameliorate stimulus-centered or object-centered neglect because the prism adaptation should only shift viewercentered coordinates of the task work-space. Indeed, one study revealed that prism adaptation led to improvement in pointing to midline (defined by viewer-centered coordinates) targets, but not in selecting the happier/smiling side of chimeric faces (which would plausibly depend on attention to stimulus-centered representations) (Ferber and others 2003). Realignment of a stimulus-centered reference frame (shifted to the right after right temporal cortex compromise) may depend on other methods. At least for patients with viewer-centered neglect, rehabilitation may be most effective if it focuses on both the spatial bias through realignment (e.g., achieved via prism adaptation) and recalibration (Redding and Wallace, in press). In fact, a number of studies have shown that rehabilitation directed toward increasing the size of the task workspace can reduce symptoms of neglect (Myers 1999). Similarly, increasing the size of the “attentional window” by presenting large circles in the same block of trials with small circles with left-sided or right-sided targets (gaps) improved detection of left-sided targets in the small


circles. Likewise, presenting circles to the right and left of centrally presented circles with left- and right-sided targets in the same block of trials increased detection of left-sided targets in the central circles presented alone (Hillis, Mordkoff and Caramazza 1999). Several studies have shown that increasing the size of the task work-space with stimulus-centered coordinates (e.g., by embedding a stimulus in a larger stimulus; Hillis and Selnes 1999), or by shifting the task work-space with stimuluscentered coordinates to the right of the total visual stimulus by adding irrelevant visual information on the left side of the stimulus (e.g., Hillis and Caramazza 1995), can improve stimulus-centered neglect. Together, these results suggest that rehabilitation aimed at improving either recalibration or realignment in the affected reference frame can reduce symptoms of neglect, although improvement in both is likely necessary for lasting and complete improvement. Another recent finding that holds promise for rehabilitation of neglect is the effect of pharmacological intervention. Based on the hypotheses that neglect results at least in part from reduced maintenance of attention during exploration of space, and that noradrenergic pathways are critical for vigilance, Malhotra and colleagues (in press) tested the hypothesis that guanficine, a noradrenergic agonist, would improve vigilance and performance on spatial attention tasks in patients with USN. In a double-blind trial, they found that two patients with temporoparietal damage, sparing the dorsolateral prefrontal cortex, showed improved detection of contralesional targets in sessions after guanficine administration but not in sessions after placebo administration. One patient with right dorsolateral prefrontal cortex damage (who might not be able to respond to noradrenergic modulation of vigilance) showed no response to guanficine. Although results are preliminary, owing to the small number of patients, they indicate that amelioration of the nonspatially biased aspects of attention might reduce symptoms of neglect, compatible with the twocomponent account of neglect. Finally, rTMS has been used to restore the normal balance in hemispheric rivalry. That is, inhibition of the left parietal cortex can reduce symptoms of neglect, presumably by reducing the transcollosal suppression of the already compromised right parietal cortex. Thus, a few studies have shown that rTMS over the unaffected parietal lobe improved performance on tests of USN transiently (Oliveri and others 2001) or for at least 15 days (Brighina and others 2003). Summary USN is a complex disorder of attending to specific locations in space defined with respect to the side of the viewer or the side of the stimulus or object representation to which the patient is attending. There are a number of areas of the brain that are critical to various aspects of attention; damage to areas specifically related to laterally biased spatial attention (intraparietal sulcus in either hemisphere) may result in subtle errors on the

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contralesional side in either viewer-centered or stimulus/ object-centered coordinates. However, the full syndrome of viewer-centered USN probably requires neural dysfunction of both the intraparietal sulcus and the angular gyrus/TPJ of the nondominant hemisphere—responsible for nonspatially biased attention, such as vigilance and calibration of the attentional window or task work-space. Neural dysfunction, as caused by hypoperfusion and/or infarct, of the right angular gyrus and intraparietal sulcus is associated with neglect in viewer-centered coordinates; dysfunction of STG is associated primarily with neglect in object- or stimulus-centered coordinates. A loss of the normal balance of biased spatial attention to the opposite hemispace by the intraparietal sulcus or STG can also explain various sorts of extinction caused by dysfunction of either area. Effective rehabilitation of neglect probably requires amelioration of both the spatial bias (e.g., shift of the task work-space toward the ipsilesional side and inability to realign the spatial coordinates) and nonspatially biased components of attention (vigilance and resizing of the pathologically reduced attentional window or task work-space). Pharmacological modulation of vigilance with noradrenergic agonists with concomitant traditional behavioral interventions may improve vigilance and calibration. Prism adaptation or rTMS inhibition of the contralesional parietal cortex can be helpful in ameliorating the spatial bias. References Andersen RA, Buneo CA. 2002. Intentional maps in posterior parietal cortex. Annu Rev Neurosci 25:189–220. Andersen RA, Essick GK, Siegal RM. 1985. Encoding of spatial location by posterior parietal neurons. Science 230:456–8. Arrington CM, Carr TH, Mayer AR, Rao SM. 2002. Neural mechanisms of visual attention: object-based selection of a region in space. J Cogn Neurosci 12(Suppl 2):106–17. Barbut D, Gazzaniga MS. 1987. Disturbances in conceptual space involving language and speech. Brain 110:1487–96. Barton J, Behrmann M, Black S. 1998. Ocular search during line bisection: the effects of hemi-neglect and hemianopia. Brain 121:1117–31. Baxter DM, Warrington EK. 1983. Neglect dysgraphia. J Neurol Neurosurg Psychiatry 46:1073–8. Behrmann M, Plaut DC. 2001. The interaction of spatial reference frames and hierarchical object representations: evidence from figure copying in hemispatial neglect. Cognit Affect Behav Neurosci 1:307–29. Beis JM, Keller C, Morin N, Bartolomeo P, Bernati T, Chokron S, and others. 2004. Right spatial neglect after left hemisphere stroke: qualitative and quantitative study. Neurology 63(9):1600–5. Bisiach E, McIntosh RD, Dijkerman HC, McClements KI, Colombo M, Milner AD. 2004. Visual and tactile length matching in spatial neglect. Cortex 40:651–7. Bisley JW, Goldberg ME. 2003. Neuronal activity in the lateral intraparietal area and spatial attention. Science 3;299(5603):81–6. Brighina F, Bisiach E, Oliveri M, Piazza A, La Bua V, Daniele O, and others. 2003. 1 Hz repetitive transcranial magnetic stimulation of the unaffected hemisphere ameliorates contralesional visuospatial neglect in humans. Neurosci Lett 336(2):131–3. Bushnell MC, Goldberg ME, Robinson DL. 1981. Behavioral enhancement of visual responses in monkey cerebral cortex: I. Modulation in posterior parietal cortex related to selective visual attention. J Neurophysiol 4(4):755–72.

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