The cingulate cortex and spatial neglect

Handbook of Clinical Neurology, Vol. 166 (3rd series) Cingulate Cortex B.A. Vogt, Editor https://doi.org/10.1016/B978-0-444-64196-0.00009-1 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 9

The cingulate cortex and spatial neglect A.M. BARRETT1,2,3*, ANDREW ABDOU1,4,5, AND MEGHAN D. CAULFIELD3,6 Center for Stroke Rehabilitation Research, Kessler Foundation, West Orange, NJ, United States

1

2

Kessler Institute for Rehabilitation, West Orange, NJ, United States

3

Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ, United States 4

Burke Rehabilitation Hospital, Mamaroneck, NY, United States 5

Montefiore Health System, Bronx, NY, United States

6

Department of Psychological and Brain Sciences, Villanova University, Villanova, PA, United States

Abstract Spatial neglect is asymmetric attention, orienting, and action causing functional disability. It is linked to higher-order cortical sensory processing; however, spatial motor “Aiming” processing is critical to fundamental, adaptive environmental movement and daily life function. The cingulate cortex, in particular the anterior cingulate and anterior midcingulate cortex, is strongly linked to spatial Aiming deficits and likely to predict daily life disability in spatial neglect. The authors review the impact and mechanisms of spatial neglect and then describe specific symptoms associated with spatial neglect that are theoretically linked to cingulate cortical functions or associated with lesions extending to cingulate regions in a wellcharacterized spatial neglect cohort. The treatment implications for a link between cingulate cortex spatial Aiming neglect and therapies that improve spatial action, arousal, and persistence are discussed. Clinicians may want to consider theoretically motivated treatments targeted at specific symptoms as well as use treatments supported for spatial neglect based on unselected and uncharacterized groups.

OVERVIEW The cingulate cortex plays a key role in maintaining spatial cognitive systems critical for everyday life and function. Analyzing its contributions to a healthy spatial system is important for both theoretical and pragmatic reasons. Theoretical information about cingulatemediated processes in spatial function can motivate researchers and clinicians to take a structured approach to the role of this brain region in spatial cognitive function. However, knowledge about cingulate-related networks can also generate new information about spatial neglect directly relevant for scientific-guided treatments. Because researchers often limit their consideration of spatial neglect to the classic clinical features of the

syndrome associated with other brain regions, and do not take into account the specific characteristics associated with cingulate cortical damage in spatial neglect, they may not be well prepared to address the clinical problem. A general definition of spatial neglect is asymmetric orienting and action causing functional disability (Barrett & Burkholder, 2006). It has a staggering public health impact in personal and social cost; thus cingulaterelated spatial neglect is a major problem and a burden to public health. Further, we can predict that cingulatelinked mechanisms will play a role in some, but not other, stages of information processing in spatial cognition. A spatial cognitive model that fractionates spatial motor

*Correspondence to: A.M. Barrett, MD, FAAN, FANA, FASNR, Center for Visual and Cognitive Rehabilitation Research (151R), Atlanta VA Health System, 1601 Clairmont Road, Decatur, GA 30033, United States. Tel: +1-404-321-6111, E-mail: [email protected]

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Aiming from Where, perceptual-attentional and representational spatial cognitive processing stages (Barrett, 2014) may be particularly useful as we theoretically examine the spatial deficits observed after cingulate damage. In this chapter, our first aim is to describe why it is useful to think about spatial systems that both take in (spatial Where, perceptual-attentional systems) and act upon spatial information (output or spatial motor-intentional, Aiming systems). Specific Where and Aiming stages of spatial cognitive processing are dissociable, and we can observe unique symptoms associated with spatial Where and Aiming neglect after brain injury. Spatial Aiming and motor-exploratory behaviors (Heilman, 2004; Goedert et al., 2012, 2014; Barrett & Muzaffar, 2014) may be defined as feedforward, motor-intentional, action- and movement-related spatial behaviors. Our second aim will be to examine evidence from the animal literature that spatial Aiming bias has a neuroanatomic basis. Watson et al. (1973) initiated brain–behavior analysis of spatial neglect after cingulate cortical lesions based on stages of processing. These authors proposed that alerting to environmental sensory stimulation requires intact corticofugal pathways connecting cortical oculomotor and sensory association areas to the midbrain reticular formation, via cingulate pathways. They supported this hypothesis by demonstrating that four monkeys with supplementary motor and cingulate cortical lesions failed to respond to bilateral simultaneous tactile stimulation, while they were capable of responding to single stimuli (extinction to double simultaneous stimulation, a form of spatial neglect). Interestingly, in four of the five monkeys, motor responses to a single tactile stimulus were spatially misdirected. Thus, they demonstrated a possible association between cingulate lesions and an animal model of spatial Aiming bias, which they later explored in depth in monkeys with frontal lobe lesions (Watson et al., 1978). Third, we will explore the association between the anterior cingulate and anterior midcingulate cortex (ACC and aMCC), reward and engagement, and spatial Aiming neglect. We will review how dopaminergic activation of the ACC and aMCC may be a common element linking spatial Aiming systems with the anterior part of the cingulate cortex. The ACC may support spatial Aiming functions and also arousal and persistence. We will review specific animal and human literature supporting arousal and persistence deficits as a core component of spatial neglect. In the section “Spatial Aiming Neglect and the Anterior Cingulate and Anterior Midcingulate Cortices,” we also summarize data drawn from a dataset of well-characterized patients with spatial neglect. Consistent with the critical role of the cingulate cortex in spatial Aiming functions, we found more severe spatial neglect deficits in the patient group with cingulate cortical damage, and the deficits prominently included motorexploratory bias. This suggests that spatial neglect

symptoms closely related to spatial Aiming neglect may be quite common in patients with cingulate injury. Patients with spatial neglect and cingulate cortical injury also had more severe spatial neglect on standardized testing. The MCC region may also be linked to specific spatial Aiming neglect symptoms, related to arm and hand motor recovery, and hemispatial changes in arm and hand kinesis. The posterior cingulate cortex (PCC) may have a relationship with different spatial Aiming neglect symptoms: defective motor response inhibition, directional hypokinesia of eye movements, and asymmetric approach behaviors in far space. Finally, we consider how this knowledge of dysfunctional spatial Aiming and arousal and persistence after cingulate cortical damage can be used to plan spatial neglect treatment. Standards for spatial neglect rehabilitation were derived from studies that broadly included patients with many lesion locations as well as diverse spatial neglect symptoms. Thus, although there are professional guidelines recommending care approaches for spatial neglect, we do not have protocols available specifically targeted at the cognitive deficits that occur after cingulate lesions. Our treatment summary offers choices for clinicians who wish to use a targeted, theoretically based approach to the rehabilitation of spatial neglect in patients with cingulate brain injury, addressing spatial Aiming neglect and arousal/persistence deficits.

IMPACT OF SPATIAL NEGLECT, AND STAGES-OF-PROCESSING COGNITIVE MODEL As we review information about cingulate-associated spatial neglect, we need to think about the very substantial impact of spatial neglect on public health and our society. In this section, we first examine the scope of the clinical problem of spatial neglect and its personal and social costs. We then describe a theoretical approach to spatial cognitive deficits, based upon separating input from output stages of spatial cognitive information processing. Rather than focusing exclusively on higher-order visual or perceptual-attentional sensory input systems, as has been traditional (Barrett, 2014), we will consider how cingulate-linked systems may participate in spatial Aiming functions (outputs of the spatial cognitive system). Spatial neglect occurs in the weeks after stroke in at least 50% of right brain–damaged and 30% of left brain–damaged survivors (Gainotti et al., 1972; Denes et al., 1982; Fullerton et al., 1986; Stone et al., 1993; Kalra et al. 1997; McGlone et al., 1997; Ringman et al., 2004; Hreha et al., 2010; Chen et al., 2015a,b,c). Chen et al. (2015a,b,c) reported that in patients receiving inpatient rehabilitation facility (IRF) care, spatial neglect impedes rehabilitation outcomes: burden of care due to

THE CINGULATE CORTEX AND SPATIAL NEGLECT stroke was more than 20% greater in patients with spatial neglect than in stroke survivors who did not have spatial neglect. Despite receiving more days of intensive rehabilitation, patients with spatial neglect made 13% fewer gains in functional independence than patients who did not have spatial neglect. Patients with spatial neglect experienced a slow rate of functional improvement, more than 50% slower than patients without spatial neglect. Patients with spatial neglect fell 6.5 times more often than patients without spatial neglect did. Spatial neglect prolonged IRF hospitalization by about 10 days. In this study, the cost of caring for patients with spatial neglect was also likely much higher. Total average IRF charges per person may be estimated at $1600 per day (Mayer et al., 2003). Thus, at least an additional $16,000 worth of additional costs due to prolonged length of stay could have been associated with spatial neglect in this study. Patients with spatial neglect at IRF admission were 45% less likely than those with no symptoms to go home at the end of IRF care, with more severe spatial neglect predicting long-term placement (Chen et al., 2015a,b, c). Informal family caregivers of stroke survivors with spatial neglect may also spend much more time in supervising and caring for them. In one study (Chen et al., 2017), family caregivers spent more than three times

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as much time in patient care as caregivers of stroke survivors without spatial neglect did—more than 20 h daily. Asymmetric behaviors observed in spatial neglect (see Table 9.1 and Fig. 9.1) may reflect the function of more than one stage of spatial cognitive processing, and stages of processing may reflect functions of different neuroanatomic and neuropharmacologic brain networks. There are three major categories of deficits that can be identified in spatial neglect. Spatial cognition, like all aspects of cognition, requires information to be acquired for processing via the senses and attention systems. However, information is also internally stored. Finally, systematic higher-order output-response processing also takes place as part of spatial cognition. Thus, an extremely useful overall model for spatial information processing describes how spatial information is taken into the system (spatial perceptual-attentional Where function), how it is stored internally in the form of visual images or maps (spatial representational Where function), and then how movement and action is shaped, tuned, modulated, and executed in 3D space (spatial Aiming function). An input–output, stagewise processing model can be used to study speech and language, limb praxis, and many other cognitive functions that involve both perceptual-related and motor-related

Table 9.1 Spatial cognitive processing stages and associated deficits in spatial neglect

Spatial processing stage Where, perceptual-attentional awareness (Heilman and Valenstein, 2012)

Where, representational imagery (Bisiach and Luzzatti, 1978; Halligan et al., 1992; Coslett, 1997; Bonato et al., 2016)

Aiming, motor-intentional action (Meador et al., 1986; Heilman, 2004; Barrett, 2014)

Key behaviors demonstrating bias in spatial neglect Extinction to double simultaneous stimulation Decreased vigilance in the neglected space Allochiria Right-biased visual imagery Neglect dyslexia Right bias with mental number line Directional hypokinesia Hemispatial hypokinesia Limb hypokinesia Asymmetric motor response inhibition

Frequently observed functional impairments Accidents in or outside the home Difficulty eating entire meal Failure to respond in social conversation and interaction Poor environmental navigation Illusions, difficulty recognizing objects in unfamiliar orientation, or poor visual resolution Difficulty reading Calculation errors affecting money management Veering while ambulating, either walking or in a wheelchair Augmented hemiparesis

Summarized from Barrett, A.M., Goedert, K.M., Basso, J.C., 2012. Prism adaptation for spatial neglect after stroke: translational practice gaps. Nat Rev Neurol 8 (10), 567–577. doi:10.1038/nrneurol.2012.170; Riestra, A.R., Barrett, A., 2013. Rehabilitation of spatial neglect. Handb Clin Neurol 110, 347–355. doi:10.1016/b978-0-444-52901-5.00029-0; functional impairments listed are empiric and based on clinical teaching and observations, requiring further systematic study.

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Fig. 9.1. Paper-and-pencil testing characteristic of left spatial neglect after right brain injury. At top (A), on the left, a cube presented for the patient to copy (top right) is only reproduced partially (right side only). At bottom (B), an array of lines for cancellation (Albert, 1973) presented on an 8.500  1100 horizontal sheet reveals omissions, more left-sided and more marked in near than in far space.

processing (Shallice and Cooper, 2011; Barrett, 2014). However, such a model is not yet widely employed to discuss spatial cognition. Clinical characteristics of spatial neglect may be associated with specific stages of processing (see Table 9.1). Spatial Where, perceptual-attentional errors can be attributed to asymmetric unawareness, asymmetrically abnormal habituation, asymmetric decreased vigilance, or asymmetric distraction (Goedert et al., 2012). The phenomenon of extinction, in which the patient fails to perceive a contralesional stimulus only when it is presented simultaneously with a stimulus on the ipsilesional side, may be best explained by the limited capacity of perceptual-attentional resources and is a classic sign of Where spatial cognitive dysfunction (Heilman, et al., 2000; Marzi et al., 2001; Riestra et al., 2001, 2002; Hillis et al., 2006; Beversdorf et al., 2008). Unfortunately, there is not much data yet available describing groups of subjects who have been characterized on both laboratory spatial Where and spatial Aiming tasks to understand patterns of performance of these groups on daily life functional assessment. For example, it is logical that spatial Where neglect may be the cause of errors when the patient does not notice family or clinicians

approaching in the neglected space but then greets them as soon as they cross the midline and are in the preferred body space. Where spatial errors of the representative type may occur when patients attempt to direct a helper in fetching personal effects from another room, yet only advise the helper about the objects that are positioned on the preferred side as one enters the room and omit mention of any objects that are on the neglected side. Presumably, these objects were neglected “in their mind’s eye.” Spatial Aiming errors, in their turn, might have a functional relevance in patients who lean or push toward the good side, adversely affecting posture or transfers (Shinsha and Ishigami, 1999; Riestra and Barrett, 2013). To understand how we might reduce the cost and burden of spatial neglect, we may need a system to analyze spatial neglect behaviors that relates closely to biologic factors for intervention. Although more work is needed to confirm these associations, it is quite possible that people with spatial neglect may have functional disability that arises specifically from unawareness, from inaccurate internal spatial representations, or from asymmetric orienting movements and action (Thomas and Barrett, 2019). For example, patients with spatial neglect after a right brain stroke may only eat from the right side of

THE CINGULATE CORTEX AND SPATIAL NEGLECT a plate, leaving much of the meal untouched. This might reflect a problem with detecting food on the left side of the plate. However, there is an alternate explanation. The patients might see the food on the left side of the plate and although they may be aware that it is there, they may not be able to direct actions leftward toward the food in eating—their movement repertoire may only include rightward spatial orientation. Because the only spatial movements they can initiate are rightward movements, they may be “stuck,” repeatedly taking food from the right side of the plate. The Intercollegiate Stroke Working Party in the United Kingdom (2016) warns that this bias may have a direct and adverse disabling effect, that people with stroke and spatial neglect should “be monitored to ensure that they do not eat too little through missing food on one side of the plate.” Patients with spatial neglect may also fail to dress the left side of their body, or may favor right space when navigating a wheelchair. Again, although these errors are often interpreted as perceptual or attentional (Riestra and Barrett, 2013), any of these errors might reflect either asymmetric input or asymmetric spatial output (or a combination of the two; Barrett and Burkholder, 2006; Goedert et al., 2012). It is important to consider which stage of processing is responsible for the abnormal behavior, because improvement of disability may depend directly upon whether the patient receives a treatment that is effective at altering that specific stage of spatial processing (Barrett et al., 2012). Different neuroanatomic regions might play different roles in the networks supporting the three-stage spatial cognitive processing model. Posterior, temporal–parietal cortical sensory association networks may be critical to support information input (Where, perceptual-attentional spatial cognition) or storage (Where, representational spatial cognition; Na et al., 1998), while anterior or motor-related subcortical networks may be more critical to output cognition (Spatial-motor aiming; Heilman and Valenstein, 1972; Watson et al., 1978; Na et al., 1998; Barrett et al., 1999; Sapir et al. 2007).

SPATIAL AIMING NEGLECT AND THE ANTERIOR CINGULATE AND ANTERIOR MIDCINGULATE CORTICES Dopaminergic spatial Aiming A family of characteristic symptoms are associated with spatial motor Aiming neglect and linked to dopaminergic activation. Dopaminergic brain activation, in turn, relates closely to reward networks involving the ACC and aMCC. Thus, there may be a close relationship between dysfunction in these regions, reward learning, and spatial Aiming neglect. We will first review the asymmetric motor behaviors observed in spatial Aiming neglect and their dopaminergic correlates. We will then discuss

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the relationship of these functions to ACC and aMCC damage in spatial neglect. There are a number of specific deficits we can discuss under the general category of spatial Aiming errors. A major deficit to consider is directional hypokinesia, a failure of intentional movement directed toward the neglected contralesional hemispace (Heilman et al., 1985; Bisiach et al., 1990; Coslettet al., 1990; Barrett, Crucian, and Heilman, 1999; Sapir et al., 2007). Directional hypokinesia can affect either hand and it can also affect the eyes, the trunk, and the whole body, and directional movement deficits in spatial Aiming neglect affecting the eyes, hand, arm, trunk, and whole body also include bradykinesia or hypometria (Heilman, 2004). Other specific dysfunctional movement patterns noted in spatial Aiming neglect include hemispatial hypokinesia, defined as lateralized differences in movement gain, force, or rapidity of movements depending upon the hemispace in which they are performed (Heilman and Valenstein, 1979; Goedert et al., 2012), and limb hypokinesia, which comprises abnormalities of movement performed by the contralesional limbs, beyond that accounted for by hemiparesis alone (Meador et al., 1986; Triggs et al., 1994). In addition to these deficits, patients with spatial Aiming neglect also can exhibit asymmetric perseveration, asymmetric motor impersistence, and asymmetric abnormal motor response inhibition (Kwon and Heilman, 1991, Heilman, 2004, Nys et al., 2006, Khurshid et al., 2009, Barrett, 2014). Motorexploratory behaviors, such as the ability to avoid collisions while steering and ambulating in a wheelchair, were not directly correlated with a measure of directional hypokinesia in one study (Goedert et al., 2012); however, motorexploratory behaviors are also likely part of a spatial Aiming constellation of functions. More work needs to be performed to clarify the interrelationships between these spatial-motor Aiming activities. A number of studies linked the disruption of ascending dopaminergic systems with spatial neglect and its recovery, based on animal models (Ungerstedt, 1976; Deuel and Collins, 1983) and the benefit of dopaminergic medication on generic measures of spatial neglect in human studies (Fleet et al., 1987; Mukand et al., 2001; Gorgoraptis et al., 2012). The ability to respond and turn in a contralesional direction is impaired by dopamine depletion (Carli et al. 1989), a movement bias that is distinct from a contralesional perception deficit in animals (Hoyman et al., 1979). Contralesional movement initiation is also delayed after striatal dopamine depletion in rats trained to react to sensory stimuli by making instrumental responses or head-orienting movements (Apicella et al., 1991). Contralesional orienting can be restored by dopaminergic pharmacotherapy (Schwarting and Huston, 1996). In humans, spatial movements in spatial neglect can be specifically manipulated with dopaminergic pharmacotherapy, linked with

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the spatial Aiming symptoms noted earlier, directional and hemispatial hypokinesia, and motor-exploratory behaviors (bromocriptine: Grujic et al., 1998; Barrett et al., 1999; Chaudhari et al., 2013; apomorphine: Geminiani et al., 1998). There are two links between spatial Aiming in spatial neglect and the cingulate cortex. First, the ACC/aMCC receives rich dopaminergic input (Gallagher et al., 2015), and dopaminergic subcortical–cortical connectivity to frontal and cingulate areas is important to reward and implicit learning (Jones, 1986; Jessup et al., 2010; Bissonette and Roesch, 2016; Umemoto et al., 2017). Lecce et al. (2015) proposed that the ACC may modulate visual-motor spatial behavior based on motivational/ hedonistic inputs. This group reported that a patient with spatial neglect showed severely disrupted contralesional reward learning after injury to the ACC. Consistent with this idea, the ACC is a part of a brain network activated when emotional salience enhances stimulus detection in spatial neglect (Grabowska et al., 2011). Although these papers studied patients with extremely large lesions and cingulate injury may have been a minor part of the total damage, this work still suggests that rewarding detection of salience may partly depend on processing in the ACC/aMCC regions, and in the context of handrelated motor control and pain processing, the aMCC may be very important to stimulus-driven spatial movements of the contralesional arm and hand based on pain or discomfort (Misra and Coombes, 2015). Pereira et al. (2010) demonstrated that activity in the aMCC is increased during target detection preceded by emotionally unpleasant material, with activation depending upon whether or not the participant made an overt motor response to the event. The information mentioned previously potentially links the ACC/aMCC to hemispatial and limb kinesia in spatial Aiming neglect. Weiss et al. (2003) and Ko et al. (2009) demonstrated that spatial decision and action tasks closely associated with spatial Aiming are associated with right ACC and aMCC activation, along with activation of right dorsolateral prefrontal cortex, thalamus, and left sensorimotor cortex. Prism adaptation is a treatment for spatial neglect. It involves several sessions of repeated goal-directed hand and arm movements toward a visual target. As patients look through baseright, yoked, wedge prisms, their field of view of each eye is displaced to the right. The visual shift creates a rightward movement error, which upon repeated trials is eliminated via adaptation. Once the goggles are removed, a persistent effect of the prism adaptation is strongly associated with functional improvement. Neuroimaging and neurophysiologic studies support the idea that prism adaptation therapy (PAT) affects spatial cognition and improves both impairment and daily life task performance in spatial neglect (Luaute, et al., 2006;

Barrett et al., 2012; Champod et al., 2018). Tsujimoto et al. (2018) showed that altered spatial bias after prism adaptation changes functional connectivity (FC) affecting the ACC. The study found that the FC between the right frontal eye field (FEF) and the right intraparietal sulcus was significantly decreased after PAT and that between the right FEF and the right ACC and aMCC was significantly increased after PAT and recovered within 1 h. Prism adaptation training was previously demonstrated to have a primary effect on spatial bias via altering spatial Aiming in both healthy subjects (Fortis et al., 2011a,b) and patients with spatial neglect (Fortis et al., 2011a,b). Thus, the Tsujimoto et al. (2018) study strongly suggests that the ACC is a key part of the brain network supporting spatial-motor processing, which is dysfunctional in spatial Aiming neglect.

The cingulate cortex in a cohort of patients with spatial neglect In the previous section, we suggested that ACC and aMCC may be specifically relevant to spatial Aiming and motor-intentional function. We investigated that question further via retrospective analysis in a dataset of patients who participated in a number of past research protocols investigating spatial neglect, from 2006 to the present (Clinicaltrials.gov identifiers: NCT00990353, NCT00350012, NCT00989430). These patients, who enrolled in studies of the spatial neglect syndrome after stroke had brain images from their clinical care evaluated for lesion location. Our analysis indicates that deficits of patients with spatial neglect and cingulate cortical lesions, most of which affected the ACC and MCC, were more severe and prominently include motorexploratory bias.

PARTICIPANTS We retrospectively analyzed behavioral data from 153 patients (72 female, 81 male, M ¼ 64.9 years). As part of a previous research looking at the behavioral and neuropsychologic characteristics of spatial neglect, patients completed neuropsychologic testing with the Behavioral Inattention Test-conventional subtest (BIT-c; Wilson et al., 1987), the Catherine Bergego Scale (CBS; Azouvi et al., 2003), and the Folstein Mini-Mental State Exam (MMSE; Folstein et al., 1975).

LESION MAPPING AND LOCALIZATION All participants provided informed consent consistent with the oversight of our Kessler Foundation Institutional Review Board. We examined clinical brain scans, which were obtained with participant authorization. When more than one scan was available, the scan obtained closest to the spatial neglect assessment was

THE CINGULATE CORTEX AND SPATIAL NEGLECT used. The brain scans were mapped using a “doublestrain” method that has been outlined in detail previously (Goedert et al., 2013; Chen et al., 2014). Briefly, reliability-trained technicians (blind to behavioral classifications) manually mapped individual lesions onto the axial plane of a standard brain template (Montreal Neurological Institute) using MRIcron software (Rorden et al., 2007). Normalized lesion maps were then evaluated via a consensus conference led by an independent neurologist to ensure accuracy. Lesion volume (in cubic centimeters) was calculated from the lesion map and overlaid onto a standard template for comparisons between groups. We coded cingulate damage for each patient’s lesion to identify whether the lesion crossed into the cingulate boundaries and which subregions of the cingulate cortex were involved using both Brodmann areas and Automated Anatomical Labeling (AAL) demarcations using MRIcron. Each lesion was then overlaid onto a standard brain template and the volume of cingulate lesions in subregions was extracted for analysis.

RESULTS Cingulate damage is associated with more severe spatial neglect The Behavioral Inattention Test-conventional subtest (BIT-c) is a paper-and-pencil measure of spatial neglect containing several subtests (cancellation tasks, figure copy, drawing, line bisection). BIT-c scores were available in 147 patient records. We separated patient data from these patients into a cingulate + group if any part of the brain lesion crossed into any subregion of the cingulate cortex (53 patients) and we coded patient data into a cingulate  group if there was no portion of the lesion in cingulate cortex (97 patients). A univariate ANOVA comparing groups (cingulate+, cingulate ) on BIT-c performance and using total lesion volume as a covariate indicated significant differences between the groups, F(1,147) ¼ 4.767, P < 0.05. Fig. 9.2 demonstrates that BIT-c scores were lower in the cingulate + group, suggestive of more severe spatial neglect. All of the BIT-c items except drawing were more impaired in the patients with spatial neglect, after Bonferroni correction (see Table 9.2 for summary). The Catherine Bergego Scale (CBS) is a functional performance test that captures additional variance in daily activity disability, as compared with the BIT-c (Goedert et al., 2012). One-hundred and forty-two of the patients with spatial neglect in the cohort had CBS scores in the dataset; these scores can be divided into mild neglect (0–9), moderate neglect (10–19), and severe neglect (21– 30). We divided patients into four groups by CBS score: no neglect, mild, moderate, and severe. Patients with a CBS ¼ 0 were in the spatial neglect cohort

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because they had spatial neglect on the BIT-c; the two tests are not always concordant. Using these groups in conjunction with cingulate lesion information, we conducted a chi square test to determine whether neglect severity was related to cingulate lesions. The relation between CBS group and cingulate group was significant, x2 (3, N ¼ 142) ¼ 19.21, P < 0.001; a greater proportion of patients who had severe neglect also had lesions that included the cingulate region (Fig. 9.3). Thus, this analysis confirms that cingulate stroke in our cohort was associated with more severe spatial neglect. Performance testing with the Catherine Bergego Scale suggests cingulate damage is linked to motor-exploratory errors The CBS consists of 10 items that are examiner scored by watching patients perform functional tasks, on a scale of 0 (no neglect) to 3 (severely impaired). To determine whether cingulate lesions contribute to motorexploratory symptoms of spatial neglect, we conducted independent samples t-tests. Table 9.3 shows the items of the CBS and scores between groups. Goedert et al. (2012) suggested that some CBS items are more correlated with perceptual-attentional spatial neglect and other CBS items are more correlated with motor-exploratory spatial neglect symptoms. Motor-exploratory CBS items in this prior study included the ability to dress the contralesional body, navigate in familiar places like the hospital or home, care for and anticipate the position of the contralesional body, and avoid collisions with people or objects (in bold in Table 9.3). As noted earlier, the patients with brain lesions extending into the cingulate cortex had more severe spatial neglect. When we evaluated items that were different in subjects with and without cingulate lesions, with a Bonferroni correction, three items accounted mainly for this increase in severity. Because two of the three items that accounted for increased severity in people with cingulate lesions were motor exploratory, this suggests that the patients had greater spatial-motor deficits. They also may have had greater spatial Aiming bias, since directional hypokinesia, limb hypokinesia, and hemispatial hypokinesia are likely to be closely related to motor exploration. The finding that the cingulate regions of greatest lesion overlap appear to be the ACC and aMCC regions (see Fig. 9.3) is consistent with an association of moderate–severe spatial neglect, spatial-motor deficits, and the ACC/aMCC cortex. Limitations and future directions Goedert et al. (2012) derived a factor structure for symptoms defining motor-exploratory behaviors; however, this was based on a group of patients with diverse lesions (some of whom were included in the present lesion

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BIT score (mean)

70 60 50 40 30 20 10 0 No cingulate lesion

Cingulate lesion

Fig. 9.2. BIT-c scores of patients whose lesions did not include the cingulate (n ¼ 97; left darker bar) indicate that their scores are higher (less impaired) than those having a lesion that crosses into any part of the cingulate (n ¼ 53; right lighter bar). The BIT-c is scored out of 146, and scores <130 are consistent with spatial neglect. Error bars represent 1 SEM. Table 9.2 BIT-c subtest scores for groups with and without cingulate involvement in lesions BIT-c subtest

No cingulate lesion score (SD)

Cingulate lesion score (SD)

P

Lines Letters Stars Line crossing Figure shape copying Representational drawing

4.35 (3.02) 23.64 (12.82) 33.20(17.72) 27.92 (11.02) 1.67 (1.49) 1.61 (1.16)

2.53 (2.66) 16.96 (16.90) 24.00 (16.90) 22.25 (11.35) 0.96 (1.32) 1.18 (1.26)

<0.001 a 0.003 a 0.002 a 0.003 a 0.004 a 0.036

a

Indicates significant independent samples t-test with Bonferroni correction. BIT-c, Behavioral Inattention Test-conventional.

cohort). It is possible that the factor structure for symptoms defining spatial-motor exploratory and even spatial Aiming behaviors may be different when considering only patients with cingulate lesions; evaluating validated Where and Aiming assessments and the CBS in such a group would be needed to confirm the factor structure. If a different factor structure were derived in cingulate lesions and spatial neglect, including asymmetric eating, the third item, this might reflect impairment of different components of eating skills, or qualitatively different impairment of the same skills, since eating has been demonstrated to be multistep and multidimensional functional activity (Hanna-Pladdy et al., 2003). Prospective research on patients with cingulate damage and spatial neglect, comparatively characterizing their deficits, is needed.

AROUSAL/PERSISTENCE AND THE ANTERIOR CINGULATE CORTEX The ACC may also support arousal and persistence. The anterior cingulate cortex is regarded as an essential regulating component of the alertness network and has also been associated with anticipation and preparation of attentional activity (LaBerge and Buchsbaum, 1990; Sturm et al., 1999; Thimm et al., 2006). Arousal and persistence deficits (distinct from perseveration or motor impersistence deficits that are spatial asymmetric) are closely related to the deficits of spatial neglect and commonly cooccur with the spatial neglect syndrome (Robertson, 2001). Generalized body hypokinesia is also a clinical sign cooccurring with spatial Aiming neglect (Riestra and Barrett, 2013).

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Cingulate lesion+, mild neglect (n = 11) R

Percentage of overlap 75%

R

A Cingulate lesion+, moderate neglect (n = 16) R

R

B Cingulate lesion+, severe neglect (n = 21) R

R 25%

C Fig. 9.3. Lesion overlay maps created for spatial neglect severity groups (mild (A), moderate (B), severe (C)). Analyses indicate that those participants with severe neglect also had a greater proportion of lesions that included the cingulate region (C). The right hemisphere is presented on the left side; colors range from 25% (blue) to 75% (red) of participants with overlapping lesions. Lines on the sagittal reference image (top right of each panel) indicate location of axial slices and lines on the coronal reference image (bottom right of each panel) indicate location of the sagittal slices.

An investigation on the neural correlates of spatial and nonspatial attentional subcomponents such as alerting, orienting, and reorienting of attention concluded that although behavioral data yielded clear benefits of spatial cueing, event-related data does not provide any compelling evidence for a parietal involvement in spatial

orienting. Instead, activations were found in the aMCC (Thiel et al., 2004). This suggests that aMCC-linked brain networks are responsible for this deficit when it occurs in spatial neglect. A large body of evidence indicates that the aMCC is one of the crucial brain regions engaged in the evaluative processes and in inhibiting

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Table 9.3 Subtest scores on the CBS for groups with and without cingulate lesions CBS items

No cingulate lesion score (SD)

Cingulate lesion score (SD)

P

Dressing Grooming Gaze Limb awareness Auditory Collisions Navigation Personal belongings Meals Cleaning after meal

1.33 (0.97) 0.98 (0.89) 1.56 (0.93) 1.50 (1.07) 1.11 (1.02) 1.77 (1.00) 1.29 (1.18) 1.18 (1.01) 1.02 (0.96) 0.98 (0.99)

1.88 (1.10) 1.24 (0.96) 1.96 (1.02) 1.94 (1.07) 1.37 (1.02) 2.00 (1.18) 1.98 (1.22) 1.57 (1.14) 1.70 (1.08) 1.30 (0.98)

0.003 a 1.06 0.017 0.020 0.148 0.249 0.001 a 0.038 <0.001 a 0.077

a

Indicates significant independent samples t-test with Bonferroni correction. CBS, Catherine Bergego Scale. See Azouvi et al. (2003) for a full instrument description. CBS items bolded are motor exploratory associated (Goedert et al., 2012, see text).

responses toward less desirable but easily obtainable goals in favor of more desirable goals that may also require more physical and/or mental effort (Wang et al., 2017). Therapeutic studies also support improved spatial neglect as a result of improved arousal and alertness in ACC-linked brain systems. Thimm et al. (2006) hypothesized that 3-week alertness training will increase frontal and parietal activations either ipsilesionally or contralesionally, reflecting a training-induced functional reactivation associated with training-induced amelioration of neglect symptoms. In an fMRI study they evaluated 7 right-handed patients with cortical and subcortical right hemisphere vascular lesions. All presented with stable neglect symptoms and intrinsic alertness deficit for at least 3 months. Results showed that six out of the seven subjects showed behavioral improvement on at least one of the neglect subtests immediately after training. The alertness training comprised two subroutines (“racing car” and “motorcycle”) of the attention training program “AIXTENT.” They concluded that AIXTENT alertness training game is an effective approach for the rehabilitation of spatial neglect; however, it may be necessary to prolong or even continually maintain training. Functional recovery was based on a reactivation of ipsilesional and contralesional cortical areas, including the ACC, right superior and middle frontal gyrus, other medial frontal regions, angular gyrus, and precuneus (Thimm et al., 2006). In patients having apathy but not evaluated for spatial neglect, Sasaki et al. (2017) studied 13 patients with chronic stroke assigned to either high-frequency repetitive transcranial magnetic stimulation (rTMS) over the region spanning from the MCC to medial prefrontal cortex (mPFC) or sham stimulation for 5 days. The degree of

change in an apathy scale score was significantly greater in the rTMS group than that in the sham stimulation group (Sasaki et al., 2017).

MIDCINGULATE CORTEX AND SPATIAL AIMING: LIMB KINESIS The midcingulate cortex (MCC), especially the cingulate premotor areas in the cingulate sulcus, may be particularly relevant to spatial hand and arm movements and thus limb kinesis in spatial Aiming. In the posterior MCC, learned integration of eye and head orienting toward a significant stimulus and negative affect or sensation may take place (Clark et al., 2010). The caudal cingulate premotor area also plays a major role in tuning the force and direction of movement in orienting the head and body in space (Vogt, 2016). Buklina (2002) reported that neglect was associated with cingulate-located arteriovenous malformations in 8 patients, with 4 having lesions in the MCC and 4 in the PCC. Limb hypokinesia, bradykinesia, and hypometria are all motor-intentional disorders we categorize with spatial Aiming deficits (Thomas and Barrett, 2019). As we note in Section 7, constraint-induced therapy, in which patients with hemiparesis are treated by massed practice with the paretic arm while constraint of the nonparetic arm helps to prevent substitutive use of that limb, could be considered a therapy to improve limb hypokinesia or limb-specific bradykinesia/hypometria. As such, it is interesting that Takebayashi et al. (2018) reported that improvements in arm motor assessment with constraint therapy were significantly correlated with white matter structural integrity of the motor cingulate cortex. Funayama et al. (2008) also reported limb-specific neglect symptoms in a patient with a pericallosal artery

THE CINGULATE CORTEX AND SPATIAL NEGLECT stroke, infarction of much of the corpus callosum, and cortical infarction of the MCC extending to a small part of the anterior PCC. Their patient performed paper-andpencil tests markedly differently depending upon whether the contralesional hand was used, consistent with disconnection observed in callosal neglect (Heilman and Adams, 2003); however, unlike previous patients with callosal neglect, her deficit was persistent. The authors speculated that the right cingulate lesion contributed to persistent left hemispatial kinesia with the right hand. Further information is needed to determine whether spatial Aiming deficits associated with MCC lesions are due to cortical or white matter lesions or a combination of the two, and what lesion localizations are always associated with risk. Finally, further research on the functional impact of MCC lesions in patients with spatial neglect, for example, performing bimanual tasks, is needed. Limb-specific spatial Aiming deficits would be expected to interfere with motor recovery of a paretic limb (Barrett and Muzaffar, 2014). If the MCC plays a role in motor intention (spatial Aiming) relevant to activation, use, and practice when the arm and hand is impaired, we might expect that damage to this region would predict recovery in arm motor rehabilitation studies. In patients with subcortical stroke, Li et al. (2016) and Ward et al. (2006) both reported that activation of ipsilesional MCC and white matter integrity in this region was associated with better motor task performance. Unfortunately, no spatial Aiming tasks that are sensitive to hemispatial or limb hypokinesia were used in these studies to elucidate whether improved Aiming function contributed to motor recovery.

RETROSPLENIAL AND POSTERIOR CINGULATE CORTEX IN SPATIAL APPROACH BEHAVIORS The retrosplenial cortex (RSC) extends around the splenium of the corpus callosum. Most of the RSC is found on the inferior aspect of the cingulate gyrus. It is active during the resting, mind-wandering state (Clark et al., 2010). Retrosplenial cortex has general associations with spatial function, including navigation and spatial long-term memory (Cona and Scarpazza, 2019). Takahashi (2004) reported that right RSC and adjacent PCC were associated with spatial amnesia for topographic features, with familiar locations (buildings and landscapes) recognized, though the positional relationship of these locations was lost. Patients with isolated memory impairment coupled with slight verbal and visuospatial impairments show reduced cerebral blood flow in the PCC (Clark et al., 2010). In a meta-analysis extracted from more than 11,000 functional activation

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studies in healthy controls, Huang et al. (2019) found the RSC to be associated with “spatial” function. Although their model was based on averaged regions of interest that may not have preserved anatomic distinction of cingulate regions across subjects, this suggests that the perisplenial region is a candidate hub for visual–spatial processing. Further, the PCC may have a specific relationship with spatial Aiming in spatial neglect: motor response inhibition, asymmetric eye movements, and approach behaviors in far space. Activity among the neurons within the PCC increases following saccadic eye movements, sensitive to the direction of displacement rather than the spatial location of the target (Mesulam, 1999). Neurons in PCC of macaque monkeys discharge in response to visual stimuli and following saccadic eye movements, and functional imaging in humans has described activation in PCC associated with visually guided saccades (Olson et al., 1996; Mort et al., 2003). The PCC may selectively mediate the emergence of cue-induced visuospatial expectancy, a process that entails the redistribution of motivational relevance within the extrapersonal space. This sensitivity of the PCC to cues over targets in spatial attention-shifting tasks suggests that oculomotor approach behaviors based on internal expectancies may critically involve this region. Barrett et al. (2000) and Heilman et al. (1990) reported that patients with lesions affecting the thalamicretrosplenial network for stimulus-evoked oculomotor exploration had abnormal approach behaviors in far space; if a lateral distractor appeared in far space, they would make abnormal movements toward it. Heilman et al. (1990) reported that the approach behaviors affected both oculomotor and limb movements; Barrett et al.’s (2000) patient was biased when directing limb movements. In both cases, the authors felt that retrosplenial-cingulate-thalamic-dorsolateral frontal cortical connectivity was disrupted by a brain lesion, releasing approach behaviors toward the contralesional space. Although less commonly reported than spatial neglect affecting near space, asymmetric performance in far extrapersonal space has been reported in spatial neglect (Mennemeier et al., 1992; Halligan et al., 2003; Committeri et al., 2007). Detailed information about the functional consequences of this deficit is not yet available. Both the patient with retrosplenial injury (Heilman et al., 1990) and the patient with anterior thalamic stroke (Barrett et al., 2000) had driving disability; spatial Aiming in far space may be commonly associated with this deficit. Other activities important to daily life function such as rapid ambulation or ambulating in a busy environment may also be adversely affected by approach behaviors in far space. More research is needed

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to establish whether spatial approach behaviors selective to far space after PCC and retrosplenial injury are spatial Aiming in their character, their functional skill associations, and best treatments to improve daily life performance.

A SPATIAL NEGLECT TREATMENT APPROACHES Practice guidelines A best practice to identify patients with spatial neglect across the severity continuum is to employ standardized assessment with an instrument demonstrated to predict functional disability (Intercollegiate Stroke Working Party, 2016). In patients with spatial neglect after cingulate cortical damage, severe spatial neglect may be immediately apparent during bedside observations. Patients may persistently orient rightward, sitting and lying with the trunk, eyes, and head turned to the side of their brain injury, noticeably failing to orient even to significant left-sided events such as a loud noise (Adair & Barrett, 2008). Milder spatial neglect may not be as noticeable, especially if the patient is bedbound or in an unchanging, familiar environment. For example, if a patient has a right-sided trunk, eye, and head movement bias such that the patient orients rightward about 60%–70% of the time, a clinician may not be with the patient long enough to note the asymmetry of behavior; in a hospital room, it also may not seem abnormal for the patient to be more oriented in one spatial direction because the placement of the window, television, etc., are fixed relative to a patient lying in bed. However, because of the increased safety risk and rehabilitation outcome differences that affect even patients with milder spatial neglect symptoms, we need to identify them during routine acute and postacute care. The Catherine Bergego Scale (Azouvi et al., 2006; Chen et al., 2012, 2015a) is an examiner-related scale, rating a patient’s observed asymmetry while executing daily life functional tasks. Patients are scored based on the ability to orient, respond, and act leftward, and this scale has excellent external and predictive validity. If a performance scale with external validity is used to screen for spatial neglect, this may address underimplementation of treatment for spatial neglect, because a practice that is currently common is to assign treatment based on the individual clinician’s knowledge and judgment rather than a fixed criterion. Performing a functional assessment will increase uniformity of implementation and allow clinicians to broaden their concept of spatial neglect beyond a rigid concept of spatial neglect of this disorder as a problem with vision or attention (Barrett et al., 2012).

Special considerations for patients with damage to cingulate cortex In the earlier sections, we suggested that spatial Aiming neglect, or spatial neglect affecting motor-intentional, action, and movement systems, may be particularly characteristic of the deficits people with cingulate cortical damage experience when they have disorders of spatial cognition. Implementing the systematic approach mentioned earlier is particularly important to identify spatial neglect associated with cingulate cortical damage. Our group (Riestra and Barrett, 2013; Thomas and Barrett, 2019) suggested that spatial Aiming deficits, motor-exploratory problems, and problems with arousal may be particularly difficult for clinicians to identify. Despite its high prevalence after stroke, spatial neglect is undetected in more than 60% of patients during routine clinical care (Edwards et al., 2006). If cingulateassociated spatial neglect manifests with spatial-motor rather than the typical visual or perceptual omission errors, a systematic, uniform process of assessment that includes functional performance will be even more important for rapid diagnosis and acute treatment. Although the strongest evidence for spatial Aiming deficits may implicate aMCC, where the cingulate premotor areas are located in the cingulate sulcus, there is also some association between the cingulate premotor areas and limb hypokinesis, as discussed earlier. In treating patients with spatial neglect after cingulate cortical lesions, the association between this neuroanatomic system and spatial Aiming deficits produces a second concern for the clinician. That concern is that “evidence-based” approaches recommended for spatial neglect patients did not take into account the differences in response to treatment that might be observed across patients with different symptom patterns (Barrett et al., 2012; Champod et al., 2019). This is an overall problem with using randomized controlled trials, meta-analyses, and systematic reviews to determine the care of individual patients: a treatment with best outcomes for groups of average patients is often a poor choice for a patient who is atypical in one or more major characteristics (Berguer, 2004).

Rationale for treatment selection: Translational stratification A recent Cochrane review (Bowen et al., 2013) concluded that there is not yet sufficient evidence for selecting one spatial neglect treatment over another, based on currently available randomized controlled trials and other systematic treatment studies. However, this review does not consider translational stratification to be relevant to treatment effectiveness; like most Cochrane reviews, it examines aspects of research rigor

THE CINGULATE CORTEX AND SPATIAL NEGLECT (e.g., blinding, randomization) as the possible primary source of differences in treatment outcomes between randomized controlled trials of treatments. We disagree with this philosophy (Goedert et al., 2013). Based on our extensive experience with evaluating and treating patients with spatial neglect after stroke, we observed subject heterogeneity to be the result of true differences in subject characteristics and of problems with reliability or validity of outcome evaluation. In this case, whether spatial Where or spatial Aiming brain systems are more responsible for spatial neglect-related disability—a fundamental difference in the neurologic characteristics of the deficit being treated—must be specifically measured and stratified; otherwise, variance in outcomes drastically reduces the ability to detect a treatment effect. We observed this in three systematic studies (Chen et al., 2014; Goedert et al., 2014, 2018), in which we observed that (1) patients with spatial Aiming neglect responded more readily to prism adaptation therapy (PAT), (2) patients with frontal lobe lesions also responded more readily to PAT, and (3) measures sensitive to functional movements in daily life performance, which we anticipated would be the functional correlate of spatial Aiming bias, were best to stratify stroke patients. As we described in Barrett et al. (2012) and Riestra and Barrett (2013), a failure to evaluate patients with spatial Aiming neglect separately from other spatial neglect patients in randomized controlled trials could well explain the lack of effectiveness observed in several studies of spatial neglect treatment and, in fact, may also explain Bowen et al.’s (2013) decision not to recommend specific treatment approaches in the Cochrane review. Because spatial cognitive impairments differ depending upon the dysfunctional stage of processing, a treatment acting on spatial Where spatial cognitive systems (for example, increasing the gain or enhancing the signal-noise ratio for left-sided stimuli to address leftsided unawareness) may have absolutely no effect on spatial Aiming neglect. Delivering this treatment to a diverse group of patients with spatial neglect, many of whom have primarily spatial Aiming deficits, could result in the incorrect conclusion that it is ineffective, even if the group with primarily perceptual-attentional Where deficits respond well. The averaged group outcome in this case could be entirely determined by the kind of deficits the patients who are included in the study group have. Unfortunately, we do not yet have large-scale studies of spatial Where and spatial Aiming characteristics in spatial neglect to aid in ensuring that representative groups are included in spatial neglect treatment trials. However, in the case of spatial neglect associated with cingulate cortical lesions, based on our retrospective analysis of spatial neglect patient data, we feel motor-exploratory deficits are likely to account for significant disability.

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Thus even though professional guidelines provide several options for spatial neglect treatment based on benefit in randomized controlled trials (Table 9.4, left side), we suggest that the clinician strongly consider (1) prism adaptation treatment and (2) limb activation therapy for patients with spatial neglect and lesions in the ACC and MCC. Although only a small amount of preliminary information is available supporting pharmacologic intervention, we also recommend that clinicians consider this approach in selected cases and consider applying it with appropriate caution, using either dopaminergic or stimulant medications.

PRISM ADAPTATION THERAPY Prism adaptation has been used for many years to study motor learning and implicit/procedural processing (Redding and Wallace, 2006). A rehabilitation approach using prism adaptation, PAT, is a treatment technique having patients with spatial neglect after right brain stroke wear yoked optical wedge prisms that shift what they see 11.4 degrees rightward (Frassinetti et al., 2002). An occluder blocks the first part of their arm and hand movement from view (Goedert et al., 2012, 2018) and patients complete 20-min sessions of visually guided movement practice. In the protocol used in our program (Fig. 9.4; Barrett and Houston, 2019; Barrett et al., 2019), patients mark lines and circles in left, central, and right space. Prisms are worn only for 20-min sessions; the entire protocol of treatment is 10 sessions over 14 days. Both the American Heart Association (AHA) and the American Occupational Therapy Association list this treatment in their practice guidelines for spatial neglect (Table 9.4); the AHA provides recommendation category Class IIa, Level A (reasonable to recommend treatment, supported by multiple randomized clinical trials) for this guideline for cognitive rehabilitation treatment of spatial neglect, although other spatial neglect treatments were included in AHA recommendations as a generic list. The impact of PAT on daily life disability was reviewed by Champod et al. (2018), who listed more than 20 controlled studies reporting improvement in functional disability including improved reading, ambulation, and self-care via either direct assessment or selfreport with standardized instruments reliable and validated for use in stroke. The prism adaptation process consists of three steps: (1) pointing to targets without glasses in the direction of visual targets to obtain reference values (pretest); (2) 50–60 aiming movements in the direction of visual targets with prisms that deviate the environment about 10 degrees to the right (prismatic exposure); at this stage, the movements are deviated toward the right and then the subject progressively corrects errors; and (3) aiming

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Table 9.4 Conventional spatial neglect treatment (left two columns), based on practice guidelines, is not specific to impaired spatial cognitive mechanisms

Conventional spatial neglect treatment

Targeted approach to improve spatial Aiming and arousal/ activation

Reference

Approach

Reference

Approach

Wolf and Nilsen (2015) Winstein et al. (2016) Intercollegiate Stroke Working Party (2016)

Prism adaptation training (Frassinetti et al., 2002; Chen et al., 2014)

Prism adaptation training (Fortis et al., 2011a,b; Goedert et al., 2014)

Veterans Administration/ Dept. of Defense (2010) Intercollegiate Stroke Working Party (2016)

Compensatory self-mediated cuing strategies (Niemeier et al., 2001; Walker et al., 2012)

Limb activation (Robertson and North, 1993; Làdavas et al. 1997; Eskes and Butler, 2006)

Veterans Administration/ Dept. of Defense (2010) Wolf and Nilson (2015) Winstein et al. (2016) Intercollegiate Stroke Working Party (2016)

Visual scanning training (Katz et al., 2005; Polanowska et al., 2009)

Dopaminergic and noradrenergic medications (Gorelick et al., 2011; Riestra and Barrett, 2013)

Reduce spatial motor Aiming bias by improving directional hypokinesia Reduce spatial motor Aiming bias by improving hypokinesia of the contralesional limb Improve arousal, generative behavior, persistence

In treating patients with cingulate cortical lesions, this may reduce functional benefit. Both practice guidelines and a targeted approach to spatial neglect treatment (right two columns) support prism adaptation training; however, other approaches, not mentioned in practice guidelines (right column), target cingulate-related deficits. See Champod, Eskes, and Barrett (2019) and Riestra and Barrett (2013) for further reading.

Fig. 9.4. Prism adaptation treatment (PAT) procedure, using the Kessler Foundation Prism Adaptation Treatment (KF-PAT®) Portable Kit, patent pending. Figure credit: Andrew Abdou.

toward visual targets without the prisms to measure the aftereffects (Frassinetti et al., 2002). In other words, patients with left neglect after right brain stroke initially wear prisms that displace the visual scene rightward, causing them to misreach to the right of a target. After repeated pointing, and once they have adapted such that they reach accurately, the prisms are removed, leaving patients with a leftward pointing error (Li and Malhotra, 2015). Standard programs intended to improve spatial neglect have one or two daily prism adaptation sessions over a period of 1–2 weeks (Frassinetti et al., 2002). Because studies suggest that patients with spatial Aiming neglect and frontal lobe lesions may experience the most

benefit from treatment with PAT, it is appropriate to reassess patients to confirm treatment benefit. Prism adaptation treatment has the advantage of requiring little training to administer, and patients do not need to understand and accept behavioral modification because the approach trains actions implicitly rather than relying on strategy or knowledge building. Limb activation Limb activation therapy (Robertson and North, 1993; Robertson et al., 2002) and the massed practice to the paretic limb of constraint-induced movement therapy

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(CIMT) (Mark and Taub, 2002) could all be considered treatments to increase a propensity to move with strokeaffected limbs, and thus potential treatments for limb akinesia. For limb activation therapy, patients are encouraged to make a small movement with the contralesional arm or body; this can be reinforced using a device (Robertson et al., 2002; Fong et al., 2013); however, a device is not required—verbal urging to use the “bad” arm is also effective (Eskes and Butler, 2006). Movements are encouraged and reinforced for repeated sessions: Robertson et al. (2002) used 45-min sessions weekly for 12 weeks. In practice, we have found these treatments difficult to implement for patients with spatial neglect. In using limb activation, active, effective movements on the contralesional side require patient agency and active initiation; thus considerable time can be spent in discussing with patients, who have no awareness of the deficit, why they are being asked to perform these actions, reducing time available for the therapy itself. Passive movement of the limb is not helpful (Robertson and North, 1993). Thus the treatment is very time-intensive for therapists and caregivers, who also require special training to implement it consistently. The use of limb activation training in spatial neglect is not necessarily limited to a formal limb activation protocol. Punt et al. (2011) investigated the effect of spatial cueing and limb activation on wheelchair use. They found improved midline navigation when the joystick was mounted on the contralesional side. This suggests that limb activation–based therapeutic benefits can be obtained during routine wheelchair training, based on optimal configuration of the wheelchair joystick equipment.

time, on-medication assessment specific to spatial Aiming deficits has only been performed in 5 patients treated with dopamine agonists (Geminiani et al., 1998; Barrett et al., 1999); this needs to be completed in groups of patients and response on functional parameters should be compared with spatial Aiming deficits, patient lesion location, and time since stroke as well as spatial neglect and stroke severity. The patient reported in Barrett et al. (1999) was not tested using a functional performance assessment on medication; however, his performance on line bisection, which in past research (Friedman, 1990) was associated with functional disability, was worse on medication. Grujic et al. (1998) noted that three patients exhibited increased ipsilesional exploratory eye movements on a laboratory task; these patients were not functionally characterized. Thus we do not know if their spatial bias met criteria for spatial neglect at baseline, if the finding was a laboratory phenomenon only, or if different changes in functional disability occurred on medication that may have been dissociated from performance on the laboratory task. The paradoxical worsening on laboratory tasks noted by Barrett et al. (1999) and Grujic et al. (1998), although only reported in a preliminary fashion, suggests that clinicians using dopaminergic medication should periodically reassess patients as they are titrating dopaminergic medications and certainly reassess patients on the goal dose to confirm beneficial effects. We strongly recommend using a functional performance assessment such as the Catherine Bergego Scale to obtain results maximally relevant to daily life disability.

DOPAMINERGIC PHARMACOTHERAPY

Guanfacine, an alpha-2 adrenergic agonist used to treat hypertension and attention deficit disorder and available in the United States in generic form only, may specifically improve motor-exploratory deficits, which we previously related to functional disability (Goedert et al., 2012) and which may be related to spatial motor Aiming systems. The medication improved visual search in spatial neglect patients; however, it was effective in patients without frontal damage (Li and Malhotra, 2015). Malhotra et al. (2006) also showed lesion-specific efficacy of guanfacine: it improved leftward exploration in two patients with temporoparietal lesions, but not in another patient with a frontal lesion. These authors proposed that increasing dorsolateral prefrontal cortex– mediated vigilance may improve spatial neglect symptoms in patients with motor-exploratory deficits and posterior cortical injuries (Malhotra et al., 2006). More work needs to be done investigating whether other subcortical lesions, e.g., white matter injury, interfere with or interact with guanfacine effect.

Dopaminergic pharmacotherapy may improve spatial neglect in humans, and neglect symptoms sensitive to dopaminergic supplementation may be identified with intentional premotor exploratory function (Fleet et al., 1987; Coslett et al., 1990; Tegner and Levander, 1991; Barrett et al., 1999; Mukand et al., 2001; Mapstone et al., 2003; Heilman, 2004). Rotigotine, a dopamine agonist with relatively high affinity for D1 receptors (Gorgoraptis et al., 2012), improved visual search and selective attention, without improving spatial representational functions such as working memory. However, these authors did not examine tasks in which spatial Aiming bias could be dissociated from spatial Where perceptual or representational errors. In other studies, dopaminergic medication improved only certain symptoms of spatial neglect; it might also worsen neglect in some patients (Geminiani et al. 1998; Grujic et al., 1998; Barrett et al., 1999). At this

STIMULATION OF AROUSAL

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There is very preliminary information available for a few other stimulants; however, group studies in patients with spatial neglect and patients classified by spatial Aiming versus spatial Where bias are not yet available. In a study of healthy volunteers, modafinil, but not methylphenidate, decreased the rightward bias in a perceptual task apparently mediated by an increase in right hemisphere–mediated alertness (Dodds et al., 2009). Methylphenidate, which affects both norepinephrine and dopamine, had favorable results in a case report, but its effects were inferior and shorter acting than those of bromocriptine (Hurford et al., 1998). There has been reported improvement in magnitude estimation using modafinil, a psychostimulant with probable dopaminergic effects (Volkow et al., 2009) in 1 patient with spatial neglect symptoms (Woods et al., 2006). If clinicians choose to try these agents (for example, because of lack of availability of prism adaptation or intolerance of dopaminergic medication), they should exercise great caution, as when using any nonstandard approach for which only case study and case series data are available. Reassessing spatial function and functional disability on the medication is a minimum standard for good clinical practice in these cases.

CONCLUSIONS In this chapter, we described the spatial neglect syndrome, its impact, and a translational approach to analysis and treatment of the problem based on analyzing the stage of cognitive processing that is dysfunctional in different subgroups of patients. This is potentially useful because stratification by impaired mechanism is likely to reveal different responses to restorative treatments based on the targeted action of the treatment (Goedert et al., 2014). We then discussed cingulate regions and their associated clinical characteristics relevant to spatial neglect. We retrospectively examined our own dataset of patients with brain lesion mapping and spatial neglect assessment, and our data suggests an association between spatial-motor, exploratory deficits and cingulate lesions in patients with severe spatial neglect. Finally, we described evidence for a therapeutic approach for spatial neglect generally and how a clinician may wish to modify this approach to prioritize therapies that optimally treat the symptoms of neglect likely to be associated with cingulate lesions. We discuss targeted neglect treatments that may be optimal when patients have lesions affecting a given anatomic subregion of the cingulate cortex. A relationship is strongly suspected between lesions of the ACC and spatial-motor deficits, including spatial Aiming neglect. There is also a relationship between spatial motor Aiming and the dopaminergic system (Fleet et al., 1987; Coslett et al., 1990; Tegner and Levander, 1991; Barrett et al., 1999; Mukand et al., 2001;

Mapstone et al., 2003; Heilman, 2004). Moreover, the ACC contributes to arousal and persistence. Thus, interventions, including pharmacologic therapy, which stimulate arousal and sustained attention, may play an important role in treating spatial neglect with cingulate cortical lesions. A movement toward understanding brain networks— the way that multiple brain regions interact functionally— may have led to reduced interest in semiotic, symptom- and mechanism-based research on cognitive disorders and their treatments. We hope that with the rise in precision medicine—which in its essence is patient centered—more information will be generated about specific spatial cognitive processing associated with cingulate systems and about specific limitations in activity and participation. Then, biologic scientists and clinicians can work together to understand and remediate specific functional deficits that become the focus of treatment.

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