Subliminal modulation of voluntary action experience: A neuropsychological investigation.

Human voluntary actions are often associated with a distinctive subjective experience termed 'sense of agency'. This experience could be a reconstructive inference triggered by monitoring one's actions and their outcomes, or a read-out of brain processes related to action preparation, or some hybrid of these. Participants pressed a key with the right index finger at a time of their own choice, while viewing a rotating clock. Occasionally they received a mild shock on the same finger. They were instructed to press the key as quickly as possible if they felt a shock. On some trials, trains of subliminal shocks were also delivered, to investigate whether such subliminal cues could influence the initiation of voluntary actions, or the subjective experience of such actions. Participants' keypress were always followed by a tone 250 ms later. At the end of each trial they reported the time of the keypress using the rotating clock display. Shifts in the perceived time of the action towards the following tone, compared to a baseline condition containing only a keypress but no tone, were taken as implicit measures of sense of agency. The subliminal shock train enhanced this "action binding" effect in healthy participants, relative to trials without such shocks. This difference could not be attributed to retrospective inference, since the perceptual events were identical in both trial types. Further, we tested the same paradigm in a patient with anarchic hand syndrome (AHS). Subliminal shocks again enhanced our measure of sense of agency in the unaffected hand, but had a reversed effect on the 'anarchic' hand. These findings suggest an interaction between internal volitional signals and external cues afforded by the external environment. Damage to the neural pathways that mediate interactions between internal states and the outside world may explain some of the clinical signs of AHS.

Education protects against cognitive changes associated with multiple sclerosis.

PURPOSE: Although neuropsychological impairments are common in Multiple Sclerosis (MS), the manifestation of cognitive deficits may vary greatly across MS patients. Here, we explored the influence of cognitive reserve proxy indices (education and occupation) and perceived fatigue on cognitive performance. METHODS: Fifty relapsing-remitting MS patients were evaluated. Cognitive performance was measured using the Paced Auditory Serial Addition Test (PASAT), in which information processing speed can be manipulated by varying the presentation speed of stimuli. RESULTS: MS patients with low education performed worse than healthy controls at faster PASAT speeds. By contrast, no difference was observed between MS patients with high education and matched healthy controls, regardless of PASAT speed. Moreover, we found that neither occupational attainment nor perceived fatigue has an influence on MS patients' cognitive performance. CONCLUSION: These findings provide evidence that higher education could be protective against MS-associated cognitive deficits and that high speed PASAT versions are more suitable for identifying compensatory capacities compared to low speed PASAT versions.

Low-frequency rTMS promotes use-dependent motor plasticity in chronic stroke: a randomized trial.

OBJECTIVE: To investigate the long-term behavioral and neurophysiologic effects of combined time-locked repetitive transcranial magnetic stimulation (rTMS) and physical therapy (PT) intervention in chronic stroke patients with mild motor disabilities. METHODS: Thirty patients were enrolled in a double-blind, randomized, single-center clinical trial. Patients received 10 daily sessions of 1 Hz rTMS over the intact motor cortex. In different groups, stimulation was either real (rTMS(R)) or sham (rTMS(S)) and was administered either immediately before or after PT. Outcome measures included dexterity, force, interhemispheric inhibition, and corticospinal excitability and were assessed for 3 months after the end of treatment. RESULTS: Treatment induced cumulative rebalance of excitability in the 2 hemispheres and a reduction of interhemispheric inhibition in the rTMS(R) groups. Use-dependent improvements were detected in all groups. Improvements in trained abilities were small and transitory in rTMS(S) patients. Greater behavioral and neurophysiologic outcomes were found after rTMS(R), with the group receiving rTMS(R) before PT (rTMS(R)-PT) showing robust and stable improvements and the other group (PT-rTMS(R)) showing a slight improvement decline over time. CONCLUSION: Our findings indicate that priming PT with inhibitory rTMS is optimal to boost use-dependent plasticity and rebalance motor excitability and suggest that time-locked rTMS is a valid and promising approach for chronic stroke patients with mild motor impairment. CLASSIFICATION OF EVIDENCE: This interventional study provides Class I evidence that time-locked rTMS before or after physical therapy improves measures of dexterity and force in the affected limb in patients with chronic deficits more than 6 months poststroke.

Dynamic size-change of peri-hand space through tool-use: spatial extension or shift of the multi-sensory area.

Several studies in humans and non-human primates have shown that tool-use can expand near peripersonal space (Farnè & Làdavas, 2000; Iriki, Tanaka, & Iwamura, 1996). In humans, the extension of the near peripersonal space is revealed by an increase in the severity of cross-modal extinction caused by visual stimulation at the distal edge of a rake after its use as a reaching tool. The crucial question addressed here concerns whether the dynamic re-sizing of the peri-hand space in humans constitutes a real spatial expansion of visual-tactile peri-hand area along the tool axis. Alternatively, it could constitute a shift of the integrative area from the hand towards the distal edge of the tool, or the formation of a novel visual-tactile integrative area at the same distal location (Holmes, Calvert, & Spence, 2004). We contrasted the alternative predictions made by these hypotheses in a group of RBD patients by probing, at different locations along the tool axis, the changes induced by tool-use on cross-modal extinction. By assessing the visual-tactile extinction near the hand, midway along the tool, and at the distal edge of the tool we found an increase in visual-tactile extinction after tool-use both at the middle and the distal location along the tool axis. In contrast, no change intervened at the hand proximity. These findings support the view that the tool-use dependent re-mapping of peri-hand space in humans consists of a continuous elongation of visual-tactile peri-hand area from the hand towards the tip of the tool.

Central executive system impairment in traumatic brain injury.

The aim of the present study was to identify cognitive functions affected by traumatic brain injury (TBI) and to verify the mechanism underlying cognitive impairment. More precisely, cognitive deficits following TBI can be considered as a consequence of (a) a speed processing deficit, that is a general slowing of perceptual, motor and cognitive subroutines; (b) an impairment of the Central Executive System of working memory (CES).Thirty-seven patients were submitted to a neuropsychological battery, aimed to evaluate different cognitive functions. Results showed severe deficits in speed processing, divided attention,working memory, executive functions and long term memory. Regression analyses, performed to test the two hypotheses, showed that the working memory deficit hypothesis is able to explain divided attention, executive functions and long term memory deficits more than speed processing hypothesis.

A rehabilitative program for central executive deficits after traumatic brain injury.

Deficits affecting Central Executive System (CES) of working memory (WM) are the main neuropsychological outcome after traumatic brain injury (TBI) and can also explain deficits in other domains, like divided attention, executive functions and long-term memory. For this reason we developed a rehabilitative program based on CES functions and we expected to find an improvement in WM as well as in those cognitive functions controlled by the CES. The experimental group was composed by 9 TBIs, selected for WM deficits, whereas the control group was composed by 6 TBIs, without WM deficits, but with speed processing deficits. All patients performed a cognitive training, based on PASAT (Gronwall & Wrightson, 1981)and two new versions of this task. The results showed in the experimental group an improvement in WM and in the cognitive functions controlled by the CES, whereas control patients did not show any improvement after the cognitive training.

Patterns of spontaneous recovery of neglect and associated disorders in acute right brain-damaged patients.

OBJECTIVES: The evolutionary pattern of spontaneous recovery from acute neglect was studied by assessing cognitive deficits and motor impairments. Detailed lesion reconstruction was also performed to correlate the presence of and recovery from neglect to neural substrates. METHODS: A consecutive series of right brain-damaged (RBD) patients with and without neglect underwent weekly tests in the acute phase of the illness. The battery assessed neglect deficits, neglect-related deficits, and motor impairment. Age-matched normal subjects were also investigated to ascertain the presence of non lateralised attentional deficits. Some neglect patients were also available for later investigation during the chronic phase of their illness. RESULTS: Partial recovery of neglect deficits was observed at the end of the acute period and during the chronic phase. Spatial attention was impaired in acute neglect patients, while non spatial attentional deficits were present in RBD patients with and without acute neglect. A strong association was found between acute neglect and fronto-parietal lesions. Similar lesions were associated with neglect persistence. In the chronic stage, neglect recovery was paralleled by improved motor control of the contralesional upper limb, thus emphasising that neglect is a negative prognostic factor in motor functional recovery. CONCLUSIONS: These findings show that spatial attention deficits partially improve during the acute phase of the disease in less than half the patients investigated. There was an improvement in left visuospatial neglect at a later, chronic stage of the disease, but this recovery was not complete.

Hemispatial neglect: Subtypes, neuroanatomy, and disability.

OBJECTIVE: To assess the relative frequency of occurrence of motor, perceptual, peripersonal, and personal neglect subtypes, the association of neglect and other related deficits (e.g., deficient nonlateralized attention, anosognosia), and the neuroanatomic substrates of neglect in patients with right hemisphere stroke in rehabilitation settings. METHODS: The authors assessed 166 rehabilitation inpatients and outpatients with right hemisphere stroke with measures of neglect and neglect subtypes, attention, motor and sensory function, functional disability, and family burden. Detailed lesion analyses were also performed. RESULTS: Neglect was present in 48% of right hemisphere stroke patients. Patients with neglect had more motor impairment, sensory dysfunction, visual extinction, basic (nonlateralized) attention deficit, and anosognosia than did patients without neglect. Personal neglect occurred in 1% and peripersonal neglect in 27%, motor neglect in 17%, and perceptual neglect in 21%. Neglect severity predicted scores on the Functional Independence Measure and Family Burden Questionnaire more accurately than did number of lesioned regions. CONCLUSIONS: The neglect syndrome per se, rather than overall stroke severity, predicts poor outcome in right hemisphere stroke. Dissociations between tasks assessing neglect subtypes support the existence of these subtypes. Finally, neglect results from lesions at various loci within a distributed system mediating several aspects of attention and spatiomotor performance.

Deficit of auditory space perception in patients with visuospatial neglect.

There have been many studies of visuospatial neglect, but fewer studies of neglect in relation with other sensory modalities. In the present study we investigate the performance of six right brain damaged (RBD) patients with left visual neglect and six RBD patients without neglect in an auditory spatial task. Previous work on sound localisation in neglect patients adopted measure of sound localisation based on directional motor responses (e.g., pointing to sounds) or judgement of sound position with respect to the body midline (auditory midline task). However, these measures might be influenced by non-auditory biases related with motor and egocentric components. Here we adopted a perceptual measure of sound localisation, consisting in a verbal judgement of the relative position (same or different) of two sequentially presented sounds. This task was performed in a visual and in a blindfolded condition. The results revealed that sound localisation performance of visuospatial neglect patients was severely impaired with respect to that of RBD controls, especially when sounds originated in contralesional hemispace. In such condition, neglect patients were always unable to discriminate the relative position of the two sounds. No difference in performance emerged as a function of the visual condition in either group. These results demonstrate a perceptual deficit of sound localisation in patients with visuospatial neglect, suggesting that the spatial deficits of these patients can arise multimodally for the same portion of external space.

Passive limb movements improve visual neglect.

Recent studies have reported that left neglect can be ameliorated during active movements of a contralesional limb in the contralesional space. In contrast, a passive left hand movement does not seem to induce an amelioration of neglect, at least when it is associated to simultaneous active right movement (Robertson IH, North N, Neuropsychologia 31 (1993) 293-300). In the present study, we explored the possibility that a complex passive movement, such as abduction and adduction of the arm, is able to reduce neglect also when it is associated to simultaneous active right arm movements. To test this hypothesis neglect patients were required to perform an object cancellation test and a line bisection test by using the right hand, while the left arm was passively moved. Moreover, we verified the possibility that left arm stimulation activates the peripersonal more than the extrapersonal space, with the exception of the condition in which the far space can be reached by a tool that extends peripersonal space in the far space (Farnè A, Làdavas E, Neuroreport 11 (2000) 1645-1649). For this reason, patients were required to perform the tasks in near (70 cm) and in far (140 cm) space by means of a light pen (pointing task) and of a stick (reaching task). When the left arm was passively moved the results showed a significant reduction of neglect with respect to the baseline condition, and the improvement equally affected the near and the far space. A different effect for the near and far space was observed in relation to the task (pointing vs. reaching). In the pointing task, neglect was more severe in the far than in near space; however, this difference disappeared when the patients had to reach objects by means of a stick. In conclusion, the present study shows that the entity of improvement of visual neglect due to a left passive movement is related to the entity of proprioceptive signals specifying left hand position.

Auditory peripersonal space in humans: a case of auditory-tactile extinction.

Animal experiments have shown that the spatial correspondence between auditory and tactile receptive fields of ventral pre-motor neurons provides a map of auditory peripersonal space around the head. This allows neurons to localize a near sound with respect to the head. In the present study, we demonstrated the existence of an auditory peripersonal space around the head in humans. In a right-brain damaged patient with tactile extinction, a sound delivered near the ipsilesional side of the head extinguished a tactile stimulus delivered to the contralesional side of the head (cross-modal auditory-tactile extinction). In contrast, when an auditory stimulus was presented far from the head, cross-modal extinction was dramatically reduced. This spatially specific cross-modal extinction was found only when a complex sound like a white noise burst was presented; pure tones did not produce spatially specific cross-modal extinction. These results show a high degree of functional similarity between the characteristics of the auditory peripersonal space representation in humans and monkeys. This similarity suggests that analogous physiological substrates might be responsible for coding this multisensory integrated representation of peripersonal space in human and non-human primates.

Lexical processes and eye movements in neglect dyslexia.

Neglect dyslexia is a disturbance in the allocation of spatial attention over a letter string following unilateral brain damage. Patients with this condition may fail to read letters on the contralesional side of an orthographic string. In some of these cases, reading is better with words than with non-words. This word superiority effect has received a variety of explanations that differ, among other things, with regard to the spatial distribution of attention across the letter string during reading. The primary goal of the present study was to explore the interaction between attention and lexical processes by recording eye movements in a patient (F.C.) with severe left neglect dyslexia who was required to read isolated word and non-word stimuli of various length. F.C.'s ocular exploration of orthographic stimuli was highly sensitive to the lexical status of the letter string. We found that: (1) the location to which F.C. directed his initial saccade (obtained approximately 230 ms post-stimulus onset) differed between word and non-word stimuli; (2) the patient spent a greater amount of time fixating the contralesional side of word than non-word strings. Moreover, we also found that F.C. failed to identify the left letters of a string despite having fixated them, thus showing a clear dissociation between eye movement responses and conscious access to orthographic stimuli. Our data suggest the existence of multiple interactions between lexical, attentional and eye movement systems that occur from very initial stages of visual word recognition.

Ventriloquism in patients with unilateral visual neglect.

Can visual stimuli that go undetected, because they are presented in the extinguished region of neglect patients' visual field, nevertheless shift in their direction the apparent location of simultaneous sounds (the well-known 'ventriloquist effect')? This issue was examined using a situation in which each trial involved the simultaneous presentation of a tone over loudspeakers, together with a bright square area on either the left, the right or both sides of fixation. Participants were required to report the presence of squares, and indicate by hand pointing the apparent location of the tone. Five patients with left hemineglect consistently failed to detect the left square, either presented alone or together with another square on the right. Nevertheless, on bimodal trials with a single undetected square to the left, their sound localization was significantly shifted in the direction of that undetected square. By contrast, in bimodal trials with either a single square on the right or a square on each side, their sound localization showed only small and non-significant shifts. This particular result might be due to a combination of low discrimination of lateral sound deviations with variable individual strategies triggered by conscious detection of the right square. The important finding is the crossmodal bias produced by the undetected left visual distractors. It provides a new example of implicit processing of inputs affected by unilateral visual neglect, and on the other hand is consistent with earlier demonstrations of the automaticity of crossmodal bias.

Left tactile extinction following visual stimulation of a rubber hand.

In close analogy with neurophysiological findings in monkeys, neuropsychological studies have shown that the human brain constructs visual maps of space surrounding different body parts. In right-brain-damaged patients with tactile extinction, the existence of a visual peripersonal space centred on the hand has been demonstrated by showing that cross-modal visual-tactile extinction is segregated mainly in the space near the hand. That is, tactile stimuli on the contralesional hand are extinguished more consistently by visual stimuli presented near the ipsilesional hand than those presented far from it. Here, we report the first evidence in humans that this hand-centred visual peripersonal space can be coded in relation to a seen rubber replica of the hand, as if it were a real hand. In patients with left tactile extinction, a visual stimulus presented near a seen right rubber hand induced strong cross-modal visual-tactile extinction, similar to that obtained by presenting the same visual stimulus near the patient's right hand. Critically, this specific cross-modal effect was evident when subjects saw the rubber hand as having a plausible posture relative to their own body (i.e. when it was aligned with the subject's right shoulder). In contrast, cross-modal extinction was strongly reduced when the seen rubber hand was arranged in an implausible posture (i. e. misaligned with respect to the subject's right shoulder). We suggest that this phenomenon is due to the dominance of vision over proprioception: the system coding peripersonal space can be 'deceived' by the vision of a fake hand, provided that its appearance looks plausible with respect to the subject's body.

Dynamic size-change of hand peripersonal space following tool use.

Humans and monkeys share similar sensory integrated processing of tactile and peri-hand visual inputs for coding peripersonal space surrounding the hand. In monkeys, tool use is known to induce a transient elongation of hand-centred peripersonal space along the tool axis. Here we report evidence that, also in humans, the use of a tool can increase the spatial extent of the representation of peri-hand visual space to incorporate the tool. We investigated this phenomenon in patients with tactile extinction, by using a cross-modal paradigm well suited to reveal visual-tactile integration near patients' hand. In the present study cross-modal extinction was assessed far from patients' ipsilesional hand, at the distal edge of a hand-held rake. We found that cross-modal extinction was more severe after patients used the rake to retrieve distant objects with respect to a condition in which the rake was not used. This evidence of an expansion of peri-hand space lasted only a few minutes after tool use. By contrast, peri-hand space expansion was not observed when motor actions towards distant objects did not involve the tool. These findings show that visual peri-hand space has important dynamic properties in humans; it can be expanded and contracted depending upon tool use.

Seeing or not seeing where your hands are.

Previous findings have demonstrated the existence of a visual peripersonal space centered on the hand in humans and its modulatory effects on tactile perception. A strong modulatory effect of vision on touch perception was found when a visual stimulus was presented near the hand. In contrast, when the visual stimulus was presented far from the hand, only a weak modulatory effect was found. The aim of the present study was to verify whether such cross-modal links between touch and vision in the peripersonal space centered on the hand could be mediated by proprioceptive signals specifying the current hand positions or if they directly reflect an interaction between two sensory modalities, i.e., vision and touch. To this aim, cross-modal effects were studied in two different experiments: one in which patients could see their hands and one in which vision of their hands was prevented. The results showed strong modulatory effects of vision on touch perception when the visual stimulus was presented near the seen hand and only mild effects when the vision of the hand was prevented. These findings are explained by referring to the activity of bimodal neurons in premotor and parietal cortex of macaque, which have tactile receptive fields on the hand, and corresponding visual receptive fields in the space immediately adjacent to the tactile fields. One important feature of these bimodal neurons is that their responsiveness to visual stimuli delivered near the body part is reduced or even extinguished when the view of the body part is prevented. This implies that, at least for the hand, the vision of the hand is crucial for determining the spatial mapping between vision and touch that takes place in the peripersonal space. In contrast, the proprioceptive signals specifying the current hand position in space do not seem to be relevant in determining the cross-modal interaction between vision and touch.

Neuropsychological evidence of an integrated visuotactile representation of peripersonal space in humans.

Current interpretations of extinction suggest that the disorder is due to an unbalanced competition between ipsilesional and contralesional representations of space. The question addressed in this study is whether the competition between left and right representations of space in one sensory modality (i.e., touch) can be reduced or exacerbated by the activation of an intact spatial representation in a different modality that is functionally linked to the damaged representation (i.e., vision). This hypothesis was tested in 10 right-hemisphere lesioned patients who suffered from reliable tactile extinction. We found that a visual stimulus presented near the patient"s ipsilesional hand (i.e., visual peripersonal space) inhibited the processing of a tactile stimulus delivered on the contralesional hand (cross-modal visuotactile extinction) to the same extent as did an ipsilesional tactile stimulation (unimodal tactile extinction). It was also found that a visual stimulus presented near the contralesional hand improved the detection of a tactile stimulus applied to the same hand. In striking contrast, less modulatory effects of vision on touch perception were observed when a visual stimulus was presented far from the space immediately around the patient"s hand (i.e., extrapersonal space). This study clearly demonstrates the existence of a visual peripersonal space centered on the hand in humans and its modulatory effects on tactile perception. These findings are explained by referring to the activity of bimodal neurons in premotor and parietal cortex of macaque, which have tactile receptive fields on the hand and corresponding visual receptive fields in the space immediately adjacent to the tactile fields.

In search of biased egocentric reference frames in neglect.

The present study was aimed at assessing, by means of visual as well as proprioceptive-kinaesthetic straight-ahead tasks, the possible causal role of the ipsilesional deviation of the egocentric reference frame in determining neglect syndrome. The hypothesis, originally proposed by Ventre et al. [3], that an alteration of the representation of body-centred space can be a cause of asymmetrical spatial behaviour in humans has been recently revived by Karnath and co-workers [24]. The results of the present study seem to challenge the view that a systematic ipsilesional displacement of the egocentric reference is the crucial mechanism responsible for unilateral visual neglect. Under visual conditions, in which patients were required to stop a moving spot as it crossed their perceived midline, the ipsilesional deviation of the egocentric reference frame was dependent upon the direction of visual scanning. Right to left visual scanning direction produced a rightward displacement of the egocentric reference. In contrast, left to right visual scanning direction allowed neglect patients to correctly locate their perceived egocentre with an accuracy which did not differ from controls. The notion that the effect of a deviation of the egocentric reference frame is actually dependent on a bias in the visual scanning orienting response was also confirmed in the proprioceptive straight-ahead pointing tasks, in which the patients were blindfolded and therefore no visual information was available. In these conditions, in which patients were required to judge the subjective midline by using head, trunk and shoulder co-ordinate systems, the displacement of the subjective egocentric midline was not present.

Neuropsychological evidence of the functional integration of visual, auditory and proprioceptive spatial maps.

We infer the functional integration of the visual, auditory and proprioceptive spatial maps from the behaviour of a patient (G.A.) with left visual neglect, i.e. a derangement of visual space representation. G.A. was required to point manually to left, centre or right acoustic stimuli, under visual control or blindfolded, with the responding hand (left or right) located either on the left, centre or right space. G.A.'s manual pointing responses to left auditory stimuli were strongly influenced by the visual spatial information and by the proprioceptive spatial information related to the position of the responding effector. In the visual control condition, when the patient performed the task with the left effector located on the left, pointing responses to left auditory stimuli were shifted towards the right intact visual space. In contrast, when the visual spatial information was rendered less salient, i.e. in the blindfolded condition, and the effector was again located on the left, manual pointing responses were confined to the previously ignored left space. These findings are consistent with the view that the acoustic representation is modulated by the impaired visual representation and by the proprioceptive spatial map related to the position of the responding effector.

Visual peripersonal space centred on the face in humans.

A convergent series of studies in monkeys and man suggests that the computation of visual space is performed in several brain regions for different behavioural purposes. Among these multiple spatial areas, the ventral intraparietal cortex, the putamen and the ventral aspect of the premotor cortex (area 6) contain a system for representing visual space near the face (peripersonal space). In these cerebral areas some neurons are bimodal: they have tactile receptive fields on the face, and they can also be driven by visual stimuli located near the tactile field. The spatial correspondence between the visual and tactile receptive fields provides a map of near visual space coded in body-part-centred co-ordinates. In the present study we demonstrate for the first time the existence of a visual peripersonal space centred on the face in humans. In patients with right hemispheric lesions, visual stimuli delivered in the space near the ipsilesional side of the face extinguished tactile stimuli on the contralesional side (cross-modal visuotactile extinction) to the same extent as did an ipsilesional tactile stimulation (unimodal tactile extinction). Furthermore, a visual stimulus presented in the proximity of the contralesional side of the face improved the detection of a left tactile stimulus: i.e. under bilateral tactile presentation patients were more accurate to report the presence of a left tactile stimulus when a simultaneous visual stimulus was presented near the left side of the face. However, when visual stimuli were delivered far from the face, visuotactile extinction and visuotactile facilitation effects were dramatically reduced. These findings are consistent with the hypothesis of a representation of visual peripersonal space coded in bodypart-centred co-ordinates, and they provide a striking demonstration of the modularity of human visual space.