Elsevier

Cortex

Volume 62, January 2015, Pages 73-88
Cortex

Special issue: Research report
Cingulate neglect in humans: Disruption of contralesional reward learning in right brain damage

https://doi.org/10.1016/j.cortex.2014.08.008Get rights and content

Abstract

Motivational valence plays a key role in orienting spatial attention. Nonetheless, clinical documentation and understanding of motivationally based deficits of spatial orienting in the human is limited. Here in a series of one group-study and two single-case studies, we have examined right brain damaged patients (RBD) with and without left spatial neglect in a spatial reward-learning task, in which the motivational valence of the left contralesional and the right ipsilesional space was contrasted. In each trial two visual boxes were presented, one to the left and one to the right of central fixation. In one session monetary rewards were released more frequently in the box on the left side (75% of trials) whereas in another session they were released more frequently on the right side. In each trial patients were required to: 1) point to each one of the two boxes; 2) choose one of the boxes for obtaining monetary reward; 3) report explicitly the position of reward and whether this position matched or not the original choice. Despite defective spontaneous allocation of attention toward the contralesional space, RBD patients with left spatial neglect showed preserved contralesional reward learning, i.e., comparable to ipsilesional learning and to reward learning displayed by patients without neglect. A notable exception in the group of neglect patients was L.R., who showed no sign of contralesional reward learning in a series of 120 consecutive trials despite being able of reaching learning criterion in only 20 trials in the ipsilesional space. L.R. suffered a cortical-subcortical brain damage affecting the anterior components of the parietal-frontal attentional network and, compared with all other neglect and non-neglect patients, had additional lesion involvement of the medial anterior cingulate cortex (ACC) and of the adjacent sectors of the corpus callosum. In contrast to his lateralized motivational learning deficit, L.R. had no lateral bias in the early phases of attentional processing as he suffered no contralesional visual or auditory extinction on double simultaneous tachistoscopic and dichotic stimulation and detected, with no exception, single contralesional visual and auditory stimuli. In a separate study, we were able to compare L.R. with another RBD patient, G.P., who had a selective lesion in the right ACC, in the adjacent callosal connections and the medial-basal prefrontal cortex. G.P. had no contralesional neglect and displayed normal reward learning both in the left and right side of space. These findings show that contralesional reward learning is generally preserved in RBD patients with left spatial neglect and that this can be exploited in rehabilitation protocols. Contralesional reward learning is severely disrupted in neglect patients when an additional lesion of the ACC is present: however, as demonstrated by the comparison between L.R. and G.P. cases, selective unilateral lesion of the right ACC does not produce motivational neglect for the contralesional space.

Introduction

Assigning motivational valence to sensory stimuli and to their spatial location in the environment has a key-role in guiding the distribution of attentional resources. As originally emphasised by Mesulam, 1981, Mesulam, 1999, a major function of any attentional system is in fact that of focussing attention on locations that “harbour expected events of motivational salience”. The ability to process motivational-reward signals and to associate these signals to sensory stimuli and motor actions is based on a network of cortical and subcortical structures. Dopaminergic neurons in the ventral tegmental area (VTA), in the ventral striatum (i.e., nucleus accumbens) and neurons in the ventral medial prefrontal cortex show typical patterns of discharge in response to rewards (Bromberg-Martin et al., 2010, Matsumoto and Hikosaka, 2009, Montague et al., 1996, Platt and Huettel, 2008, Satoh et al., 2003, Schultz et al., 1997). These neurons increase their discharge in response to unpredicted rewards, hold their rate of discharge steady in response to expected rewards and show reduced discharge when no reward occurs. Through their efferent connections, these neuronal populations modulate the activity of neurons with spatially selective responses in sensory (Superior Colliculus; Ikeda & Hikosaka, 2003; V1: Shuler & Bear, 2006), attentional (Parietal cortex: Platt & Glimcher, 1999), pre-motor and motor structures (Frontal eye field, Prefrontal Cortex and Caudate Nuclei: Ding and Hikosaka, 2006, Kobayashi et al., 2002, Kobayashi et al., 2007, Roesch and Olson, 2003) and send reward signals to higher-order structures implicated in action-planning and executive control (Rushworth and Behrens, 2008, Silvetti et al., 2013, Silvetti et al., 2011). This allows a large-scale integration between motivational inputs and the neural representation of space and action. Motivational signals can have both a direct impact on sensory processing and provide the information that is necessary to keep track of reward history and to establish appropriate strategies in the exploitation of rewards as a function of their value and probability of occurrence in space and time (Della Libera and Chelazzi, 2006, Della Libera and Chelazzi, 2009, Hickey et al., 2010). These two different modalities of “sensory based” and “strategically biased” reward processing might correspond, respectively, to early and late phylogenetically developed mechanisms of cognitive control operating in parallel (Hickey et al., 2010).

Several lines of evidence point out that the medial Anterior Cingulate Cortex (ACC) has a pivotal role in reinforcement learning (Rushworth and Behrens, 2008, Silvetti et al., 2013, Silvetti et al., 2011). Neurons in the ACC are sensitive to the association between expected rewards and sensory cues or motor actions. Importantly, the ACC is also endowed with populations of neurons that respond to mismatches between expected and actual rewards, thus encoding errors in reward prediction. Altogether, the functional and computational activity of the ACC has a key role in the discovery, exploitation and updating of rewards distribution in the environment (Jessup et al., 2010, Silvetti et al., 2011). Thanks to its anatomical connectivity, the ACC is ideally suited to play this function. The ACC receives dopaminergic reward-related inputs from the midbrain and has direct cortico-cortical connections with prefrontal, parietal and temporal areas participating in the control of spatial attention (Morecraft et al., 1993, Morecraft et al., 2012). The ACC also conveys important efferent signals to the noradrenergic Locus Coeruleus (LC) complex in the midbrain (Aston-Jones & Cohen, 2005). The LC, in turn, has efferent projections to the inferior parietal and the caudal superior temporal area, thus providing a supplemental indirect pathway for the transmission of ACC signals to cortical sites involved in attentional control (Aston-Jones & Cohen, 2005). Noradrenergic signals from the LC help resetting attentional priorities when an established associative rule between reward and sensory stimuli or motor actions is no longer valuable and new associations must be explored (Aston-Jones and Cohen, 2005, Bouret and Sara, 2005). In summary, the ACC constitutes a limbic–cortical interface allowing the modulation of attentional and motor behaviour by motivational-hedonistic inputs.

A few evidences have recently suggested that improved motivation can ameliorate spatial search in right brain damaged patients affected by attentional neglect for the contralesional left side of space. Mesulam (1985) first reported the observation of one patient with severe left side neglect who showed a marked improvement in detecting targets on the left side of a letter cancellation task when he was promised with a reward of one penny for the detection of each target. Some years later, Ishiai et al. (1990) showed that neglect patient engaged in a line cancellation task improved their performance when they were requested to number rather than crossing-out lines, just as if the need to use consecutive and increasing numbers motivated patients to look for additional lines in the contralesional space. More recently, Malhotra, Soto, Li, and Russell (2013) first formally tested the original anecdotal observation reported by Mesulam (1985). Studying a group of ten neglect patients, these authors showed that promising a small monetary reward for each target found, improved the performance in a multiple item cancellation task as compared with an equivalent no-reward condition. Patients showing the lowest effects of monetary incentive had lesion centred in the right striatum.

Notwithstanding these encouraging clinical reports and the well-established knowledge on ACC functions, no study has systematically investigated whether RBD patients with spatial neglect can explicitly learn and exploit the release of rewards in the contralesional left hemispace and, eventually, to which degree contralesional reward learning is resistant to the competitive release of rewards in the ipsilesional right hemispace. Most important, it entirely remains to be established whether in humans, selective unilateral lesions of the ACC engender contralesional reward-learning deficits, i.e., motivational neglect, or whether such a disturbance arises from the combined unilateral lesion of the ACC and the adjacent parietal-frontal attentional areas that are most frequently damaged in neglect patients. Adding these pieces of knowledge to the rich literature on the neglect syndrome seems important, because ascertaining spared contralesional reward learning in neglect patients might lead to the adoption of reward-learning based rehabilitation strategies and the improvement of currently adopted rehabilitation protocols.

Here, in a series of one group- and two single-case studies, we addressed these issues using a simple reward-learning task that allows manipulating and contrasting the motivational valence of the left and the right hemispace. More specifically, in separate blocks of trials the higher motivational valence of the left hemispace was contrasted with the lower motivational valence of the right hemispace and vice versa. The results of our investigations demonstrate that RBD patients with spatial neglect can adequately appreciate and exploit the prevalent release of rewards in the contralesional space: this, however, with the notable exception of one patient who, compared to all other patients, suffered an additional lesion in the ACC and in the adjacent callosal connections.

Section snippets

Participants

We tested a sample of 14 patients with right brain damage (3 females and 11 males; mean age 60.8 SD 7.1, range 51–71 years). They were admitted for physical and neuropsychological rehabilitation at the Santa Lucia Foundation IRCCS in Rome. At the time of clinical and experimental evaluation all patients were free from confusion and from temporal and spatial disorientation. They gave written informed consent to participate in the study, which was previously approved by the local ethical

Reward learning

On average, N+ patients took 44 trials (SD 39.6) to reach learning criterion when the left box was more frequently rewarded (reward-left) and 28 trials (SD: 19.9) when the right box was more frequently rewarded (reward-right). These learning rates were equivalent [F (1,7) = 1, p = .35; η2 = .13]. N− patients took 40.8 trials (SD: 26.1) to reach criterion in the reward-left block and 55.1 trials in the reward-right block (SD 36.2). These learning rates were equivalent [F (1,5) = .35, p = .57; η2

Case study

L.R. is a right-handed 60-year-old retired marshal, who suffered a cerebral ischaemia in August 2010. The investigation we report here took place 45 days after the ischaemic event. By that time, L.R. was well oriented in time and space, cooperative and well motivated despite his left hemiplegia and being easily fatigued. His speech was well organized and he was able to correctly report his clinical history. He also complained about hemiplegia and slowness in finding things. Object naming

Study 3: Comparison of L.R. Case with that of a patient, G.P., suffering a selective lesion of the right ACC and the right medial orbitofrontal cortex

After the completion of study 1 and 2, we had the opportunity to compare the case of L.R. with the case of G.P., a patient suffering a selective lesion of the medial ACC and the adjacent callosal connections and no lesion involvement of the lateral cortical-subcortical structures that were damaged in L.R.

General discussion

In the first study of the present series of investigations, we have administered to one group of RBD patients with contralesional left spatial neglect (N+) and one group of RBD patient without neglect (N−), a simple reward-learning task in which two different behavioural conditions were contrasted. In one condition rewards were prevalently (i.e., 75% of trials) released in the left-contralesional side of space and rarely released (i.e., 25% of trials) in the ipsilesional space, whereas in the

Conclusions

To summarise, the observations reported in the present series of studies provide promising insights on the pathological anatomical and functional conditions that in right brain damaged patients lead to severe and spatially modulated deficits in the integration between motivational inputs and the representation of space and motor actions. The same set of findings demonstrate that voluntary learning and exploitation of rewards released in the contralesional space is generally spared in RBD

Funding

This work was funded by grants from the Fondazione Santa Lucia-Ministero della Salute (Italian Ministry of Health: grant RF10.091) and University of Rome “La Sapienza” – Progetto Ateneo 2013 to F.D.

Acknowledgements

The authors wish to thank Prof. Clelia Rossi-Arnaud and Prof. Paolo Bartolomeo for helpful suggestions in the revision of the manuscript.

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    Centro Ricerche di Neuropsicologia, Fondazione Santa Lucia, IRCCS, Via Ardeatina 306 – 00179 Roma, Italy.

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