Special issue: Research reportCingulate neglect in humans: Disruption of contralesional reward learning in right brain damage
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.
References (78)
- et al.
Network reset: a simplified overarching theory of locus coeruleus noradrenaline function
Trends in Neurosciences
(2005) - et al.
Dopamine in motivational control: rewarding, aversive, and alerting
Neuron
(2010) - et al.
Effects of unilateral dorsal and ventral striatal dopamine depletion on visual neglect in the rat: a neural and behavioural analysis
Neuroscience
(1989) - et al.
Investigation of the single case in neuropsychology: confidence limits on the abnormality of test scores and test score differences
Neuropsychologia
(2002) - et al.
A modified damped Richardson–Lucy algorithm to reduce isotropic background effects in spherical deconvolution
NeuroImage
(2010) - et al.
White matter (dis) connections and gray matter (dys) functions in visual neglect: gaining insights into the brain networks of spatial awareness
Cortex
(2008) - et al.
Reward-dependent gain and bias of visual responses in primate superior colliculus
Neuron
(2003) - et al.
Gambling against neglect: unconscious spatial biases induced by reward reinforcement in healthy people and brain-damaged patients
Cortex
(2013) - et al.
The Wundt-Jastrow illusion in the study of spatial hemi-inattention
Neuropsychologia
(1988) - et al.
Cytoarchitecture and cortical connections of the anterior cingulate and adjacent somatomotor fields in the rhesus monkey
Brain Research Bulletin
(2012)
Value-based modulations in human visual cortex
Neuron
A simple test of visual neglect
Neurology
An introduction to computational diffusion MRI: the diffusion tensor and beyond
An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance
Annual Review of Neuroscience
Sensitivity of clinical and behavioural tests of spatial neglect after right hemisphere stroke
Journal of Neurology, Neurosurgery & Psychiatry
Left unilateral neglect as a disconnection syndrome
Cerebral Cortex
Modulating the attentional bias in unilateral neglect: the effects of the strategic set
Experimental Brain Research
Dissociable effects of cingulate and medial frontal cortex lesions on stimulus-reward learning using a novel Pavlovian autoshaping procedure for the rat: implications for the neurobiology of emotion
Behavioral Neuroscience
Double dissociation of stimulus-value and action-value learning in humans with orbitofrontal or anterior cingulate cortex damage
The Journal of Neuroscience
Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention
Nature
Atlas of human brain connections
Prolonged neglect following unilateral disruption of a prefrontal cortical–dorsal striatal system
European Journal of Neuroscience
Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space
Journal of Computer Assisted Tomography
Payne and Jones revisited: estimating the abnormality of test score differences using a modified paired samples t test
Journal of Clinical and Experimental Neuropsychology
Visual selective attention and the effects of monetary rewards
Psychological Science
Learning to attend and to ignore is a matter of gains and losses
Psychological Science
Mapping crossing fibres of the human brain with spherical deconvolution: towards an atlas for clinico-anatomical correlation studies
Studies in cognition and rehabilitation in hemiplegia
Comparison of reward modulation in the frontal eye field and caudate of the macaque
The Journal of Neuroscience
The anatomy of neglect without hemianopia: a key role for parietal-frontal disconnection?
NeuroReport
Dopamine agonist therapy for neglect in humans
Neurology
Dopaminergic stimulation in unilateral neglect
Journal of Neurology, Neurosurgery & Psychiatry
Probability cuing of target location facilitates visual search implicitly in normal participants and patients with hemispatial neglect
Psychological Science
The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke
Brain
Dopamine agonists reorient visual exploration away from the neglected hemispace
Neurology
Reward changes salience in human vision via the anterior cingulate
The Journal of Neuroscience
The neural basis of human error processing: reinforcement learning, dopamine, and the error-related negativity
Psychological Review
Improvement of unilateral spatial neglect with numbering
Neurology
Error effects in anterior cingulate cortex reverse when error likelihood is high
The Journal of Neuroscience
Cited by (0)
- 1
Centro Ricerche di Neuropsicologia, Fondazione Santa Lucia, IRCCS, Via Ardeatina 306 – 00179 Roma, Italy.