Elsevier

Cortex

Volume 134, January 2021, Pages 265-277
Cortex

Research Report
Pupil dilation during orienting of attention and conscious detection of visual targets in patients with left spatial neglect

https://doi.org/10.1016/j.cortex.2020.10.021Get rights and content

Abstract

Right Brain-Damaged patients (RBD) with left spatial neglect (N+), are characterised by deficits in orienting and re-orienting attention to stimuli in the contralesional left side of space. In a recent ERPs study with visual stimuli (Lasaponara et al., 2018) we have pointed out that the pathological attentional bias of N+ is matched with exaggerated novelty reaction and contextual updating of targets in the right ipsilesional space and reduced novelty reaction and contextual updating of targets in the left contralesional space. To characterise further the attentional performance of N+, here we measured Pupil Dilation (PDil), which is a reliable marker of noradrenergic-locus coeruleus activity and response to unexpected events/rewards. Compared to Neutral and Valid targets, N+ patients displayed a pathological reduction of PDil in response to infrequent Invalid targets in the left side of space, while in Healthy Controls (HC) and RBD without neglect (N-) the same targets enhanced PDil with respect to Neutral and frequent Valid targets. Invalid targets in the right side of space enhanced PDil in all experimental groups. Interestingly, both N- and N+ showed a consistent number of target omissions both in the left and right side of space. With respect to seen targets, N- showed reduced PDil in response to unseen targets both in the left and right side of space. In contrast, N+ had reduced PDil in response to unseen targets in the left side of space though not in the right side, where seen and unseen targets evoked comparable levels of PDil. These results disclose, for the first time, the PDil correlates of spatial attention in left spatial neglect and suggest that the pathological attentional bias suffered by N+ might enhance the autonomic responses reflected in PDil to unseen ipsilesional stimuli. This enhancement can contribute to biasing contextual updating and predictive coding of stimuli in the ipsilesional space, thus worsening the pathological attentional bias of N+.

Introduction

Right brain damage (RBD) often produces a marked inability in orienting attention toward the left side of sensory, body and imagery space, i.e., the so-called “spatial neglect” syndrome (Bartolomeo, Thiebaut de Schotten, & Doricchi, 2007; Doricchi et al., 2009; Aiello, Merola, & Doricchi, 2013). Neglect is frequently grounded on lesions in the Middle Cerebral Artery area (MCA) that by damaging both intra and inter-hemispheric white matter connections, preclude both the integrated functioning of parietal and frontal attentional areas in the damaged hemisphere (Bartolomeo et al., 2007; Doricchi, Iaria, Silvetti, Figliozzi, & Siegler, 2007; Doricchi, de Schotten, Tomaiuolo, & Bartolomeo, 2008; Doricchi & Tomaiuolo, 2003; De Schotten et al., 2005; Lecce et al., 2015; Verdon, Schwartz, Lovblad, Hauert, & Vuilleumier, 2010) and the cross-talk with homologous areas in the intact left hemisphere (Lunven et al., 2015; Bozzali et al., 2012; Nyffeler et al., 2019). Neglect can also follow vascular damage in the Posterior Cerebral Artery area (PCA): this type of damage causes left homonymous hemianopia and a concomitant inter-hemispheric splenial disconnection. In this case severe visual neglect occurs because the spared parietal-frontal attentional areas in the right hemisphere become entirely deprived of visual inputs (Gaffan & Hornak, 1997; Lunven et al., 2015; Tomaiuolo et al., 2010). In rarer cases, neglect is caused by lesions that are limited to subcortical gray matter nuclei like the thalamus and the basal ganglia: in this case spatial neglect follows because of widespread hypofunctioning of cortical structures to which damaged subcortical structures are connected (Hier, Davis, Richardson, & Mohr, 1977; Damasio, Damasio, & Chui, 1980; Healton, Navarro, Bressman, & Brust, 1982; Stein & Volpe, 1983; Ferro, Kertesz, & Black, 1987; Perani, Vallar, Cappa, Messa, & Fazio, 1987; Caplan et al., 1990; Weiller et al. 1990, 1993; Donnan, Bladin, Berkovic, Longley, & Saling, 1991; Kumral, Kocaer, Ertu¨bey, & Kumral, 1995; Chung et al., 1996; Leibovitch et al., 1998; Karnath, Himmelbach, & Rorden, 2002; De Schotten, Tomaiuolo, Bartolomeo, & Doricchi, 2012).

Patients with neglect suffer typical disturbances in the distribution of visual-spatial attention: they miss more visual targets the more targets are eccentric in the left side space (Natale, Posteraro, Prior, & Marzi, 2005) and display a salient deficit in re-orienting attention toward targets in the contralesional left side of space once attention was initially drawn toward the ipsilesional right side (Posner, Walker, Friedrich, & Rafal, 1984). Using a Posner task with central cues that predicted the position of lateral visual targets in 80% of trials (Posner, 1980), we have recently explored the EEG correlates of cued orienting and target detection in patients with left spatial neglect (Lasaponara et al., 2018; see also Lasaponara et al. 2019; Lasaponara, Pinto, Aiello, Tomaiuolo, & Doricchi, 2019). One of the salient target-related findings was that neglect patients show a pathological enhancement in the amplitude of the anterior P3a component evoked by the infrequent Invalid targets in the right side of space, and a pathological drop in the amplitude of the same component when the same targets are presented in the left contralesional space. These results suggest exaggerated novelty reaction to infrequent/unexpected stimuli in the ipsilesional side of space together with pathological reduction in novelty reaction for equivalent stimuli in the contralesional side of space. The same patients also showed a reduction in the posterior P3b component to all type of visual targets, i.e., Valid, Neutral and Invalid, when these were presented in the left side of space. This finding suggests a generalised impairment in monitoring cue-target congruency in the contralesional neglected space, i.e., impaired contextual updating (Polich, 2007).

In the healthy observer, infrequent/novel events elicit a set of autonomic responses that include a temporary dilation of the pupil (Pupil Dilation: PDil; see Donchin et al., 1984; Nieuwenhuis, De Geus, & Aston-Jones, 2011). Neurophysiological and psychopharmacological studies (Rajkowski, 1993; Murphy, Robertson, Balsters, & O'connell, 2011; Murphy et al., 2014; Joshi, Li, Kalwani, & Gold, 2016; Suzuki & Tanaka, 2017), suggest that changes in PDil correlate to changes in Locus Coeruleus - Norepinephrine (LC-NE) activity (for review, see Bast, Poustka, & Freitag, 2018), and that PDil can therefore represent a non-invasive index of this activity. This is particularly interesting for studies of attention and reward in humans, given the role that NE plays in both of these functions. Indeed, neurophysiological studies have pointed out that NE modulates the exploration and exploitation of environmental statistical contingencies that regulate the association between perceptual or motor choices and reward (Aston-Jones & Cohen, 2005). In accord with this evidence, investigations in humans have highlighted a transient increase in PDil when the on-going cue-target or cue-reward statistical contingencies are occasionally violated (Gilzenrat, Nieuwenhuis, Jepma, & Cohen, 2010; Jepma & Nieuwenhuis, 2011; Silvetti, Seurinck, van Bochove, Verguts, 2013b; Silvetti, Seurinck, & Verguts, 2013a; Geva, Zivan, Warsha & Olchik, 2013) or when in a gambling task an observer is surprised by an unexpected outcome (whether positive or negative; Preuschoff, t Hart, & Einhauser, 2011). Similarly, to these findings, using a Posner task with frequent Valid (80%) and infrequent Invalid trials (20%), we have found that infrequent Invalid targets evoke larger PDil than frequent Valid ones and Neutral targets (Dragone et al., 2018; Lasaponara et al. 2019; Lasaponara, Pinto, et al., 2019). In contrast, when Invalid targets are as frequent as Valid ones, i.e., 50% Valid and 50% Invalid trials, the level of PDil evoked by Invalid targets is similar to that evoked by Valid or Neutral ones. Taken together, these results suggest that PDil is a reliable marker in the detection of target frequency/novelty (Dragone et al., 2018; Lasaponara et al. 2019; Lasaponara, Pinto, et al., 2019).

Based on the above-summarised evidence, in the present study we have investigated PDil during re-orienting of attention toward infrequent Invalid targets, in RBD patients with left spatial neglect and we have compared these responses to those evoked by frequent Valid targets and Neutral ones. We were particularly interested in exploring possible differences in PDil between Invalid targets presented in the right ipsilesional and in the left contralesional space. Based on our previous EEG results (Lasaponara et al., 2018), we expected to find a higher PDil response to infrequent ipsilesional Invalid targets, thus reflecting exaggerated novelty reaction and a corresponding reduction of PDil to infrequent/unexpected Invalid targets in the left side, thus reflecting pathologically reduced novelty reaction. To our knowledge, PDil during the performance of a spatial-attentional task has never been investigated in patients suffering neglect: therefore, the results of the present study could provide important clinical clues for the diagnosis and rehabilitation of the neglect syndrome.

Section snippets

Materials and method

In this section, we report how we determined our sample size, all data exclusions, all inclusion/exclusion criteria, whether inclusion/exclusion criteria were established prior to data analysis, all manipulations, and all measures in the study.

Anatomical results

The lesion probability maps resulting from the subtractions between N+ and N- showed two areas of 100% lesion overlap in N+ and no overlap, i.e., 0%, in N- patients (Fischer exact test, p = .0006). A first peak of lesion overlap was located in the white matter ventrally to the post–central gyrus and dorsally to the insula (See third row in Fig. 2: Peak A, MNI coordinates: 34, −13, 31). The second peak was located in the white matter underlying the marginal gyrus (See third row in Fig. 2: Peak

Discussion

In the present study, using a conventional Posner task with endogenous cues we sought to investigate the PDil response of N+ patients to Valid, Neutral and Invalid targets that were presented in the ipsilesional right and the contralesional left side of space. We have found that N+ patients display a pathological reduction of PDil in response to Invalid targets in the left side of space though not to Invalid targets in the right side of space. In contrast, compared with Neutral and Invalid

Credit author statement

Stefano Lasaponara: Conceptualization, Methodology, Investigation, Formal analysis and Writing - Original Draft. Gianfranco Fortunato: Software, Formal analysis, Writing- Reviewing and Editing. David Conversi: Software, Resources. Michele Pellegrino: Investigation, Resources Mario Pinto: Investigation, Resources. Donald Louis Collins: Formal analysis. Francesco Tomaiuolo: Formal analysis. Fabrizio Doricchi: Conceptualization, Methodology, Supervision, Writing - Original Draft, Writing-

Data accessibility

The conditions of our ethics approval do not permit public archiving of anonymised study data. Readers seeking access to the data should contact the corresponding author Prof. Fabrizio Doricchi ([email protected]) or the local ethics committee at IRCCS Fondazione Santa Lucia, Roma – Italy. Access will be granted to named individuals in accordance with ethical procedures governing the reuse of sensitive data. There are no specific conditions that the requestors must meet to obtain

Open Practices

The study in this article earned an Open Materials badge for transparent practices. Materials and data for the study are available at Data are available on request.

Acknowledgements

This work was supported by grants PRIN 2017 (Project number: 2017XBJN4F), Fondazione Terzo Pilastro and Università Progetti Ateneo – La Sapienza to F.D. M.P. was supported from a grant Fondazione Santa Lucia, IRCCS Roma.

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