Behavioural and functional changes in neglect after multisensory stimulation.

The present cohort study investigated whether systematic multisensory audio-visual stimulation might improve clinical signs of neglect. To this aim, patients with neglect (n = 7) and patients with neglect associated with hemianopia (n = 12) were exposed to a course of audio-visual stimulation with spatially and temporally coincident audio-visual pairs of stimuli for 10 daily training sessions (4 h of training per day), over two weeks. Performance on neuropsychological tests assessing neglect was measured before training, immediately after the training and months after the training at a follow-up session. The results showed significant post-training improvements in clinical signs of neglect, which were stable at the follow-up. These findings suggest that intensive and prolonged multisensory audio-visual stimulation affects orientation towards the neglected hemifield, therefore inducing long-term improvements in visual exploration and neglect symptoms in both patients with neglect and patients with neglect associated with hemianopia. Previous evidence from hemianopic patients suggests that these post-training effects might be mediated by activity in spared subcortical structures, such as the superior colliculus, which are relevant to multisensory integrative processing and spatial orientation.

Right Hemisphere Dominance for Unconscious Emotionally Salient Stimuli.

The present review will focus on evidence demonstrating the prioritization in visual processing of fear-related signals in the absence of awareness. Evidence in hemianopic patients without any form of blindsight or affective blindsight in classical terms will be presented, demonstrating that fearful faces, via a subcortical colliculo-pulvinar-amygdala pathway, have a privileged unconscious visual processing and facilitate responses towards visual stimuli in the intact visual field. Interestingly, this fear-specific implicit visual processing in hemianopics has only been observed after lesions to the visual cortices in the left hemisphere, while no effect was found in patients with damage to the right hemisphere. This suggests that the subcortical route for emotional processing in the right hemisphere might provide a pivotal contribution to the implicit processing of fear, in line with evidence showing enhanced right amygdala activity and increased connectivity in the right colliculo-pulvinar-amygdala pathway for unconscious fear-conditioned stimuli and subliminal fearful faces. These findings will be discussed within a theoretical framework that considers the amygdala as an integral component of a constant and continuous vigilance system, which is preferentially invoked with stimuli signaling ambiguous environmental situations of biological relevance, such as fearful faces.

Fearful faces modulate spatial processing in peripersonal space: An ERP study.

Peripersonal space (PPS) represents the region of space surrounding the body. A pivotal function of PPS is to coordinate defensive responses to threat. We have previously shown that a centrally-presented, looming fearful face, signalling a potential threat in one's surroundings, modulates spatial processing by promoting a redirection of sensory resources away from the face towards the periphery, where the threat may be expected - but only when the face is presented in near, rather than far space. Here, we use electrophysiological measures to investigate the neural mechanism underlying this effect. Participants made simple responses to tactile stimuli delivered on the cheeks, while watching task-irrelevant neutral or fearful avatar faces, looming towards them either in near or far space. Simultaneously with the tactile stimulation, a ball with a checkerboard pattern (probe) appeared to the left or right of the avatar face. Crucially, this probe could either be close to the avatar face, and thus more central in the participant's vision, or further away from the avatar face, and thus more peripheral in the participant's vision. Electroencephalography was continuously recorded. Behavioural results confirmed that in near space only, and for fearful relative to neutral faces, tactile processing was facilitated by the peripheral compared to the central probe. This behavioural effect was accompanied by a reduction of the N1 mean amplitude elicited by the peripheral probe for fearful relative to neutral faces. Moreover, the faster the participants responded to tactile stimuli with the peripheral probe, relative to the central, the smaller was their N1. Together these results, suggest that fearful faces intruding into PPS may increase expectation of a visual event occurring in the periphery. This fear-induced effect would enhance the defensive function of PPS when it is most needed, i.e., when the source of threat is nearby, but its location remains unknown.

Fear-related signals are prioritised in visual, somatosensory and spatial systems.

The human brain has evolved a multifaceted fear system, allowing threat detection to enable rapid adaptive responses crucial for survival. Although many cortical and subcortical brain areas are believed to be involved in the survival circuits detecting and responding to threat, the amygdala has reportedly a crucial role in the fear system. Here, we review evidence demonstrating that fearful faces, a specific category of salient stimuli indicating the presence of threat in the surrounding, are preferentially processed in the fear system and in the connected sensory cortices, even when they are presented outside of awareness or are irrelevant to the task. In the visual domain, we discuss evidence showing in hemianopic patients that fearful faces, via a subcortical colliculo-pulvinar-amygdala pathway, have a privileged visual processing even in the absence of awareness and facilitate responses towards visual stimuli in the intact visual field. Moreover, evidence showing that somatosensory cortices prioritise fearful-related signals, to the extent that tactile processing is enhanced in the presence of fearful faces, will be also reported. Finally, we will review evidence revealing that fearful faces have a pivotal role in modulating responses in peripersonal space, in line with the defensive functional definition of PPS.

The spatial effect of fearful faces in the autonomic response.

Peripersonal space (PPS) corresponds to the space around the body and it is defined by the location in space where multimodal inputs from bodily and external stimuli are integrated. Its extent varies according to the characteristics of external stimuli, e.g., the salience of an emotional facial expression. In the present study, we investigated the psycho-physiological correlates of the extension phenomenon. Specifically, we investigated whether an approaching human face showing either an emotionally negative (fearful) or positive (joyful) facial expression would differentially modulate PPS representation, compared to the same face with a neutral expression. To this aim, we continuously recorded the skin conductance response (SCR) of 27 healthy participants while they watched approaching 3D avatar faces showing fearful, joyful or neutral expressions, and then pressed a button to respond to tactile stimuli delivered on their cheeks at three possible delays (visuo-tactile trials). The results revealed that the SCR to fearful faces, but not joyful or neutral faces, was modulated by the apparent distance from the participant's body. SCR increased from very far space to far and then to near space. We propose that the proximity of the fearful face provided a cue to the presence of a threat in the environment and elicited a robust and urgent organization of defensive responses. In contrast, there would be no need to organize defensive responses to joyful or neutral faces and, as a consequence, no SCR differences were found across spatial positions. These results confirm the defensive function of PPS.

The spatial logic of fear.

Peripersonal space (PPS) refers to the space surrounding the body. PPS is characterised by distinctive patterns of multisensory integration and sensory-motor interaction. In addition, facial expressions have been shown to modulate PPS representation. In this study we tested whether fearful faces lead to a different distribution of spatial attention, compared to neutral and joyful faces. Participants responded to tactile stimuli on the cheeks, while watching looming neutral, joyful (Experiment 1) or fearful (Experiment 2) faces of an avatar, appearing in far or near space. To probe spatial attention, when the tactile stimulus was delivered, a static ball briefly appeared central or peripheral in participant's vision, respectively ≈1° or ≈10° to the left or right of the face. With neutral and joyful faces, simple reactions to tactile stimuli were facilitated in near rather than in far space, replicating classic PPS effects, and in the presence of central rather than peripheral ball, suggesting that attention may be focused in the immediate surrounding of the face. However, when the face was fearful, response to tactile stimuli was modulated not only by the distance of the face from the participant, but also by the position of the ball. Specifically, in near space only, response to tactile stimuli was additionally facilitated by the peripheral compared to the central ball. These results suggest that as fearful faces come closer to the body, they promote a redirection of attention towards the periphery. Given the sensory-motor functions of PPS, this fear-evoked redirection of attention would enhance the defensive function of PPS specifically when it is most needed, i.e. when the source of threat is nearby, but its location has not yet been identified.

Alpha oscillations reveal implicit visual processing of motion in hemianopia.

After lesion or deafferentation of the primary visual cortex, hemianopic patients experience loss of conscious vision in their blind field. However, due to the spared colliculo-extrastriate pathway, they might retain the ability to implicitly process motion stimuli through the activation of spared dorsal-extrastriate areas, despite the absence of awareness. To test this hypothesis, Electroencephalogram (EEG) was recorded from a group of hemianopic patients without blindsight (i.e., who performed at chance in different forced-choice tasks), while motion stimuli, static stimuli or no stimuli (i.e., blank condition) were presented either in their intact or in their blind visual field. EEG analyses were performed in the time-frequency domain. The presentation of both motion and static stimuli in the intact field induced synchronization in the theta band and desynchronization both in the alpha and the beta band. In contrast, for stimuli presented in the blind field, significantly greater desynchronization in the alpha range was observed only after the presentation of motion stimuli, compared to the blank condition, over posterior parietal-occipital electrodes in the lesioned hemisphere, at a late time window (500-800 msec). No alpha desynchronization was elicited by static stimuli. These results show that hemianopic patients can process only visual signals relying on the activation of the dorsal pathway (i.e., motion stimuli) in the absence of awareness and suggest different patterns of electrophysiological activity for conscious and unconscious visual processing. Specifically, visual processing in the absence of awareness elicits an activity limited to the alpha range, most likely reflecting a "local" process, occurring within the extrastriate areas and not participating in inter-areal communication. This also suggests a response specificity in this frequency band for implicit visual processing. In contrast, visual awareness evokes changes in different frequency bands, suggesting a "global" process, accomplished by activity in a wide range of frequencies, probably within and across cortical areas.

Posterior brain lesions selectively alter alpha oscillatory activity and predict visual performance in hemianopic patients.

Alpha oscillatory frequency and amplitude have been linked to visual processing and to the excitability of the visual cortex at rest. Therefore, posterior brain lesions, which damage the neural circuits of the visual system might induce alterations in the alpha oscillatory activity. To investigate this hypothesis, EEG activity was recorded during eyes-closed resting state in patients with hemianopia with posterior brain lesions, patients without hemianopia with anterior brain lesions and age-matched healthy controls. Patients with posterior lesions revealed a selective slowdown of individual alpha frequency in both the intact and the lesioned hemisphere and a reduction of alpha amplitude in the lesioned hemisphere, resulting in an interhemispheric imbalanced oscillatory alpha activity, while no significant alterations in the alpha range were found in patients with anterior lesions. This suggests a crucial role of posterior cortices in coordinating alpha oscillations in the visual system. Moreover, right posterior lesions had a more severe reduction of individual alpha frequency and altering of the interhemispheric distribution of the alpha amplitude, in line with the notion of the prominence of the right posterior cortices in balancing the interhemispheric functioning. Crucially, the duration of the in individual alpha frequency and the interhemispheric imbalance in alpha amplitude were directly linked to visuo-spatial performance across all participants and to impaired visual detection abilities in hemianopics, therefore supporting a functional role of alpha oscillations in visual processing and suggesting that activity in this frequency range at rest represents a neurophysiological marker reliably reflecting the integrity and the functionality of the visual system in humans.

Unseen fearful faces facilitate visual discrimination in the intact field.

Implicit visual processing of emotional stimuli has been widely investigated since the classical studies on affective blindsight, in which patients with primary visual cortex lesions showed discriminatory abilities for unseen emotional stimuli in the absence of awareness. In addition, more recent evidence from hemianopic patients showed response facilitation and enhanced early visual encoding of seen faces, only when fearful faces were presented concurrently in the blind field. However, it is still unclear whether unseen fearful faces specifically facilitate visual processing of facial stimuli, or whether the facilitatory effect constitutes an adaptive mechanism prioritizing the visual analysis of any stimulus. To test this question, we tested a group of hemianopic patients who perform at chance in forced-choice discrimination tasks of stimuli in the blind field. Patients performed a go/no-go task in which they were asked to discriminate simple visual stimuli (Gabor patches) presented in their intact field, while fearful, happy and neutral faces were concurrently presented in the blind field. The results showed a reduction in response times to the Gabor patches presented in the intact field, when fearful faces were concurrently presented in the blind field, but only in patients with left hemispheric lesions. No facilitatory effect was observed in patients with right hemispheric lesions. These results suggest that unseen fearful faces are implicitly processed and can facilitate the visual analysis of simple visual stimuli presented in the intact field. This effect might be subserved by activity in the spared colliculo-amygdala-extrastriate pathway that promotes efficient visual analysis of the environment and rapid execution of defensive responses. Such a facilitation is observed only in patients with left lesions, favouring the hypothesis that the right hemisphere mediates implicit visual processing of fear signals.

Pulvinar Lesions Disrupt Fear-Related Implicit Visual Processing in Hemianopic Patients.

The processing of emotional stimuli in the absence of awareness has been widely investigated in patients with lesions to the primary visual pathway since the classical studies on affective blindsight. In addition, recent evidence has shown that in hemianopic patients without blindsight only unseen fearful faces can be implicitly processed, inducing enhanced visual encoding (Cecere et al., 2014) and response facilitation (Bertini et al., 2013, 2017) to stimuli presented in their intact field. This fear-specific facilitation has been suggested to be mediated by activity in the spared visual subcortical pathway, comprising the superior colliculus (SC), the pulvinar and the amygdala. This suggests that the pulvinar might represent a critical relay structure, conveying threat-related visual information through the subcortical visual circuit. To test this hypothesis, hemianopic patients, with or without pulvinar lesions, performed a go/no-go task in which they had to discriminate simple visual stimuli, consisting in Gabor patches, displayed in their intact visual field, during the simultaneous presentation of faces with fearful, happy, and neutral expressions in their blind visual field. In line with previous evidence, hemianopic patients without pulvinar lesions showed response facilitation to stimuli displayed in the intact field, only while concurrent fearful faces were shown in their blind field. In contrast, no facilitatory effect was found in hemianopic patients with lesions of the pulvinar. These findings reveal that pulvinar lesions disrupt the implicit visual processing of fearful stimuli in hemianopic patients, therefore suggesting a pivotal role of this structure in relaying fear-related visual information from the SC to the amygdala.

Decoupling of Early V5 Motion Processing from Visual Awareness: A Matter of Velocity as Revealed by Transcranial Magnetic Stimulation.

Motion information can reach V5/MT through two parallel routes: one conveying information at early latencies through a direct subcortical route and the other reaching V5 later via recurrent projections through V1. Here, we tested the hypothesis that input via the faster direct pathway depends on motion characteristics. To this end, we presented motion stimuli to healthy human observers at different velocities (4.4°/sec vs. 23°/sec) with static stimuli as controls while applying transcranial magnetic stimulation (TMS) pulses over V5 or V1. We probed for TMS interference with objective (two-alternative forced choice [2AFC]) and subjective (awareness) measures of motion processing at six TMS delays from stimulus onset (poststimulus window covered: ∼27-160 msec). Our results for V5-TMS showed earlier interference with objective performance for fast motion (53.3 msec) than slow motion (80 msec) stimuli. Importantly, TMS-induced decreases in objective measures of motion processing did correlate with decreases in subjective measures for slow but not fast motion stimuli. Moreover, V1-TMS induced a temporally unspecific interference with visual processing as it impaired the processing of both motion and static stimuli at the same delays. These results are in accordance with fast moving stimuli reaching V5 through a different route than slow moving stimuli. The differential latencies and coupling to awareness suggest distinct involvement of a direct (i.e., colliculo-extrastriate) connection bypassing V1 depending on stimulus velocity (fast vs. slow). Implication of a direct pathway in the early processing of fast motion may have evolved through its behavioral relevance.

Invisible side of emotions: somato-motor responses to affective facial displays in alexithymia.

According to recent theories, the detection of emotions involves somatic experiences. In this study, we investigated the relation between somatic responses to affective stimuli, emotion perception, and alexithymia. Variations in automatic rapid facial reactions (RFRs) were measured in a selected population of participants with high and low levels of alexithymia (HA and LA, respectively). Electromyographic activity was recorded from the corrugator supercilii and the zygomaticus major, while participants performed a gender classification task on faces expressing various emotional states. LA participants showed congruent RFRs in response to both fearful and happy stimuli. On the other hand, HA participants did not show congruent RFRs in response to fearful faces. They showed congruent, but delayed, RFRs in response to happy faces. These results provide evidence of a deficit in somato-motor emotional processing in people with high alexithymic personality traits, and thus support the hypothesis that alexithymia is associated with a deficit in emotional embodiment.

"Lacking warmth": Alexithymia trait is related to warm-specific thermal somatosensory processing.

Alexithymia is a personality trait involving deficits in emotional processing. The personality construct has been extensively validated, but the underlying neural and physiological systems remain controversial. One theory suggests that low-level somatosensory mechanisms act as somatic markers of emotion, underpinning cognitive and affective impairments in alexithymia. In two separate samples (total N=100), we used an established Quantitative Sensory Testing (QST) battery to probe multiple neurophysiological submodalities of somatosensation, and investigated their associations with the widely-used Toronto Alexithymia Scale (TAS-20). Experiment one found reduced sensitivity to warmth in people with higher alexithymia scores, compared to individuals with lower scores, without deficits in other somatosensory submodalities. Experiment two replicated this result in a new group of participants using a full-sample correlation between threshold for warm detection and TAS-20 scores. We discuss the relations between low-level thermoceptive function and cognitive processing of emotion.

Error monitoring is related to processing internal affective states.

Detecting behavioral errors is critical for optimizing performance. Here, we tested whether error monitoring is enhanced in emotional task contexts, and whether this enhancement depends on processing internal affective states. Event-related potentials were recorded in individuals with low and high levels of alexithymia-that is, individuals with difficulties identifying and describing their feelings. We administered a face word Stroop paradigm (Egner, Etkin, Gale, & Hirsch, 2008) in which the task was to classify emotional faces either with respect to their expression (happy or fearful; emotional task set) or with respect to their gender (female or male; neutral task set). The error-related negativity, a marker of rapid error monitoring, was enhanced in individuals with low alexithymia when they adopted the emotional task set. By contrast, individuals with high alexithymia did not show such an enhancement. Moreover, in the high-alexithymia group, the difference in the error-related negativities between the emotional and neutral task sets correlated negatively with difficulties identifying their own feelings, as measured by the Toronto Alexithymia Scale. These results show that error-monitoring activity is stronger in emotional task contexts and that this enhancement depends on processing internal affective states.

Compensatory Recovery after Multisensory Stimulation in Hemianopic Patients: Behavioral and Neurophysiological Components.

Lateralized post-chiasmatic lesions of the primary visual pathway result in loss of visual perception in the field retinotopically corresponding to the damaged cortical area. However, patients with visual field defects have shown enhanced detection and localization of multisensory audio-visual pairs presented in the blind field. This preserved multisensory integrative ability (i.e., crossmodal blindsight) seems to be subserved by the spared retino-colliculo-dorsal pathway. According to this view, audio-visual integrative mechanisms could be used to increase the functionality of the spared circuit and, as a consequence, might represent an important tool for the rehabilitation of visual field defects. The present study tested this hypothesis, investigating whether exposure to systematic multisensory audio-visual stimulation could induce long-lasting improvements in the visual performance of patients with visual field defects. A group of 10 patients with chronic visual field defects were exposed to audio-visual training for 4 h daily, over a period of 2 weeks. Behavioral, oculomotor and electroencephalography (EEG) measures were recorded during several visual tasks before and after audio-visual training. After audio-visual training, improvements in visual search abilities, visual detection, self-perceived disability in daily life activities and oculomotor parameters were found, suggesting the implementation of more effective visual exploration strategies. At the electrophysiological level, after training, patients showed a significant reduction of the P3 amplitude in response to stimuli presented in the intact field, reflecting a reduction in attentional resources allocated to the intact field, which might co-occur with a shift of spatial attention towards the blind field. More interestingly, both the behavioral improvements and the electrophysiological changes observed after training were found to be stable at a follow-up session (on average, 8 months after training), suggesting long-term effects of multisensory audio-visual training. These long-lasting effects seem to be subserved by the activation of the spared retino-colliculo-dorsal pathway, which promotes orienting responses towards the blind field, able to both compensate for the visual field loss and concurrently attenuate visual attention towards the intact field. These results add to previous findings the knowledge that audio-visual multisensory stimulation promote long-term plastic changes in hemianopics, resulting in stable and long-lasting ameliorations in behavioral and electrophysiological measures.

Reduced anticipation of negative emotional events in alexithymia.

Alexithymia is characterized by difficulties in different domains of emotion processing, especially in relation to negative emotions. Nevertheless, its causal mechanisms remain elusive. Reduced anticipation of negative emotional events might be one such mechanism because it enables the individual to prepare to respond effectively to coming events. To test this, changes in skin conductance response (SCR) were recorded during classical fear conditioning in sixty participants with high (HA), medium (MA) and low (LA) levels of alexithymia. Two coloured squares were presented, one was reinforced with a mild electrical stimulation (CS+) while the other was never reinforced (CS-). Critically, despite all groups showing higher SCR to CS+ compared to CS-, SCR to CS+ was lower and extinguished earlier in HA compared to MA and LA. These differences appeared to be attributable neither to differences in the intensity of stimulation received, nor to SCR to the stimulation itself. Groups showed comparable SCR to CS- as well. Therefore, HA exhibited decreased anticipation of the occurrence of a negative emotional event. Disruption of this mechanism may then compromise effective emotion recognition, emotional response and response regulation, which characterise HA, and represent a unifying causal mechanism underlying the difficulties in emotion processing of this group.

The role of the retino-colliculo-extrastriate pathway in visual awareness and visual field recovery.

Patients with visual field defects resulting from post-chiasmatic lesions experience loss of visual function in up to one half of their visual field, with consequent impairments in their daily life activities. Therefore, effective strategies for compensating for the visual field loss are of great clinical relevance. After lesions to the primary visual pathway -which conveys visual information from the retina to the lateral geniculate nucleus, the optic radiations and, then, to the striate cortex-an alternative visual pathway, which projects from the superior colliculus to the extrastriate cortex, is usually spared in patients with visual field defects. In the present review, evidence for spared functioning of this alternative pathway in patients with visual field defects will be presented, both in terms of residual visual abilities, without awareness, for stimuli presented in the blind field, and the ability to integrate unseen visual signals presented in the blind field with concurrent auditory stimuli. Crucially, this review will discuss how the spared retino-colliculo-extrastriate pathway might be a useful tool for compensating for the loss of visual perception. Accordingly, evidence for the compensatory effects of systematic multisensory audio-visual stimulation in patients with visual field defects will be reviewed.

Audio-visual multisensory training enhances visual processing of motion stimuli in healthy participants: an electrophysiological study.

Evidence from electrophysiological and imaging studies suggests that audio-visual (AV) stimuli presented in spatial coincidence enhance activity in the subcortical colliculo-dorsal extrastriate pathway. To test whether repetitive AV stimulation might specifically activate this neural circuit underlying multisensory integrative processes, electroencephalographic data were recorded before and after 2 h of AV training, during the execution of two lateralized visual tasks: a motion discrimination task, relying on activity in the colliculo-dorsal MT pathway, and an orientation discrimination task, relying on activity in the striate and early ventral extrastriate cortices. During training, participants were asked to detect and perform a saccade towards AV stimuli that were disproportionally allocated to one hemifield (the trained hemifield). Half of the participants underwent a training in which AV stimuli were presented in spatial coincidence, while the remaining half underwent a training in which AV stimuli were presented in spatial disparity (32°). Participants who received AV training with stimuli in spatial coincidence had a post-training enhancement of the anterior N1 component in the motion discrimination task, but only in response to stimuli presented in the trained hemifield. However, no effect was found in the orientation discrimination task. In contrast, participants who received AV training with stimuli in spatial disparity showed no effects on either task. The observed N1 enhancement might reflect enhanced discrimination for motion stimuli, probably due to increased activity in the colliculo-dorsal MT pathway induced by multisensory training.

Viewing the body modulates both pain sensations and pain responses.

Viewing the body can influence pain perception, even when vision is non-informative about the noxious stimulus. Prior studies used either continuous pain rating scales or pain detection thresholds, which cannot distinguish whether viewing the body changes the discriminability of noxious heat intensities or merely shifts reported pain levels. In Experiment 1, participants discriminated two intensities of heat-pain stimulation. Noxious stimuli were delivered to the hand in darkness immediately after participants viewed either their own hand or a non-body object appearing in the same location. The visual condition varied randomly between trials. Discriminability of the noxious heat intensities (d') was lower after viewing the hand than after viewing the object, indicating that viewing the hand reduced the information about stimulus intensity available within the nociceptive system. In Experiment 2, the hand and the object were presented in separate blocks of trials. Viewing the hand shifted perceived pain levels irrespective of actual stimulus intensity, biasing responses toward 'high pain' judgments. In Experiment 3, participants saw the noxious stimulus as it approached and touched their hand or the object. Seeing the pain-inducing event counteracted the reduction in discriminability found when viewing the hand alone. These findings show that viewing the body can affect both perceptual processing of pain and responses to pain, depending on the visual context. Many factors modulate pain; our study highlights the importance of distinguishing modulations of perceptual processing from modulations of response bias.