Bi-hemispheric transcranial direct current stimulation for upper-limb hemiparesis in acute stroke: a randomized, double-blind, sham-controlled trial.

BACKGROUND AND PURPOSE: Neuromodulation is a promising approach to increasing motor recovery in stroke; however, to date, there is a scarcity of evidence documenting the clinical potential of transcranial direct current stimulation (tDCS) administered in the acute phase of stroke. The present study aims to examine the clinical effects of a treatment involving the application of tDCS in the acute stage post-stroke. METHODS: This was a randomized, double-blind, sham-controlled trial. A cohort of 32 stroke patients with severe motor impairment underwent 5 days of treatment with real or sham bi-hemispheric tDCS over the motor cortex. During the treatment, tDCS was applied twice per day (two daily applications each of 15 min), starting 48 to 72 h after stroke onset. RESULTS: We found statistically significant improvements after both real and sham tDCS treatments in primary (hand grip strength, Motricity Index) and secondary (National Institutes of Health Stroke Scale score, Barthel Index) outcomes. Patients receiving real tDCS showed a larger improvement of upper-limb muscle strength at the end of treatment phase; this advantage was no longer present after 6 months. CONCLUSIONS: Transcranial direct current stimulation may be used to accelerate the rate of upper-limb motor recovery during the spontaneous recovery period.

Facial macrosomatognosia and pain in a case of Wallenberg's syndrome: selective effects of vestibular and transcutaneous stimulations.

Macro- and micro-somatognosia refer to rare disorders of the cerebral representation of the body whereby patients perceive body parts as disproportionately large or small. Here we report the experimental study of a patient who, following a left lateral medullary stroke (Wallenberg's syndrome, including vestibular deficits) complained of a persistent somatosensory illusory sensation of swelling, confined to the left side of his face (i.e., left macrosomatognosia). This hemifacial somatosensory distortion was associated with a left facial anesthesia, and a neuropathic pain affecting the three branches of the left trigeminal nerve. In this study, we first document quantitatively the patient's somatosensory illusion by using a somatosensory-to-visual matching task in which the patient modified the picture of his own face to fit his left-sided somatosensory misperception. The patient's performance revealed that macrosomatognosia was confined to the second branch of the left trigeminal nerve. Perception of the size of visual objects was comparatively preserved. Second, we investigated the effects of two peripheral stimulations, which may affect the spatial component of somatosensory deficits (caloric vestibular stimulation, CVS; transcutaneous electrical nervous stimulation, TENS) and pain (TENS). Left CVS abolished the facial somatosensory illusion, for about 30min, but had no effect on the left facial pain. Conversely, left TENS substantially reduced the neuropathic pain during stimulation, but had no effect on macrosomatognosia, indicating a double dissociation between the two disorders. These results reveal that facial macrosomatognosia may be regarded as a high-order deficit of somatosensory perception of the shape and volume of the face, which fits the definition of 'hyperschematia' (i.e., when the body takes up too much room) originally proposed by Bonnier (1905). Our data also indicate that CVS may favor the restoration of the conscious representation of the shape and size of the face. Overall, these findings lend support to the view that afferent inputs from the vestibular system can affect in a specific fashion the activity of cerebral structures involved in the building up and updating of the topological description of body parts.

Supercalifragilisticexpialidocious: how the brain learns words never heard before.

Vocabulary acquisition is such a major aspect of language learning in children, but also in adults when learning a foreign language, that a dedicated vocabulary learning device may exist within the language organ. To identify the relevant brain systems, we performed regional cerebral blood flow measurements in normal subjects while they were learning a list of neologisms or a list of word-nonword pairs. Structures implicated in phonological short-term memory (Broca's area, left temporo-parietal junction) were steadily activated during nonwords learning, while the left temporal lobe neocortical and paralimbic structures (parahippocampal region), associated with long-term memory, contributed to learning in a time-dependent manner, with maximal activation at the beginning of the process. The neural system specifically activated when learning new vocabulary was strongly lateralized to the left hemisphere. This evidence refines current models of memory function and supports theories which emphasise the importance of phonological competence in hemispheric dominance for language.

When the whole is more than the sum of the parts: evidence from visuospatial neglect.

One possible pathological mechanism underlying the rightward bisection error of right-brain-damaged patients with left spatial neglect is a leftward relaxation of the spatial representational medium. This view was originally based on the finding that patients with left neglect, required to extend horizontal segments, in order to double their original length, may exhibit a relative left overextension of the drawn lines (Bisiach et al., 1994). We investigated this putative distortion of representational space using a 16 cm 'line segmentation' task (Experiment I). Were the representation of space relaxed contralesionally, a progressive increase from right to left of the size of the drawn segments would be expected. Right-brain-damaged patients with left unilateral neglect (N=12) performed the segmentation task with no left versus right differences, as right-brain-damaged patients without neglect (N=8), and neurologically unimpaired control subjects (N=10), did. Experiments 2 and 3 explored the effects of sample length (1, 2, 4, and 8cm), by which the 16cm lines had to be segmented. Neglect patients produced longer left-sided segments only for the 8 cm sample (i.e. half of the length of the segment). This set of experiments suggests an impairment in the segmentation task only with the larger (8 cm) sample, when a more global level of processing may be involved. Experiment 4 assessed this hypothesis by a 'part/whole' bisection task, using 8 cm lines, presented either embedded in a longer 16 cm line or in isolation. Neglect patients made a larger rightward bisection error when the segment was not embedded. The suggestion is made that the lateral distortion of the representation of space in neglect patients (i.e., a leftward relaxation of the spatial medium) concerns tasks where a more 'global' representation of the visual stimulus has to be set up. The different demands of the segmentation and bisection tasks are discussed.

Left size distortion (hyperschematia) after right brain damage.

OBJECTIVE: To quantitate a size distortion involving the side of space contralateral to the lesion (contralesional) in two right-brain-damaged patients. METHODS: We studied two right-brain-damaged patients with lesions sparing the occipital lobe and a mild left neglect on target cancellation or line bisection. The lesions involved the temporoparietal region (Patient 1) and the basal ganglia and the insula (Patients 1 and 2). Patients were given drawing tasks and tasks requiring perceptual and visuomotor judgments of horizontal extent. RESULTS: In drawing objects such as a daisy both from memory and by copying, patients exhibited a disproportionate enlargement of the left-hand side of objects and added more left-sided petals to the drawn daisy. This pathologic behavior persisted when the patients were blindfolded and was likely to reflect a perceptual, rather than premotor, size distortion. In a task requiring the perceptual matching of two rectangles, patients underestimated the left-sided stimulus. In a visuomotor task requiring the reproduction of the horizontal extent of a segment, patients exhibited a hyperextension, when a leftward movement was required. CONCLUSIONS: We showed a disordered representation of extrapersonal space, possibly involving a contralesional relaxation of the spatial medium. The deficit does not arise at the level of retinotopic coordinate frames and is independent of unilateral spatial neglect.

Left caloric vestibular stimulation ameliorates right hemianesthesia.

BACKGROUND: Left caloric vestibular stimulation (CVS) transiently reduces impairments of right-brain-damaged patients with left unilateral neglect, including left hemianesthesia, contralateral to the side of the lesion (contralesional). Conversely, no effect on right contralesional hemianesthesia in left-brain-damaged patients is seen with right CVS. This discrepancy is unexplained. METHODS: The authors explored the effect of CVS on right- and left-brain-damaged patients with hemianesthesia. One left-brain-damaged patient had an fMRI study during tactile stimulation before and after left CVS. The same fMRI touch study, without CVS, was performed in neurologically unimpaired subjects. RESULTS: A transient remission of right hemianesthesia associated with left brain damage was observed, provided that cold CVS was administered to the left ear. In the left-brain-damaged patient studied with fMRI, left CVS modulated the neural response to right hand tactile stimuli of a portion of the secondary somatosensory area (SII) of the right hemisphere. In neurologically unimpaired subjects, fMRI scans showed that the same part of area SII in the right hemisphere was activated by ipsilateral right-sided touches and to a larger extent than area SII in the left hemisphere by left-sided touches. CONCLUSIONS: Left caloric vestibular stimulation is effective on both left and right hemianesthesia because it modulates the hemisphere that has a more complete representation of, or is capable to attend to, the whole somatosensory surface of the body. These results suggest a hardwired hemispheric asymmetry in hand representation, starting from a somatotopically organized brain region such as area SII.

Shared cortical anatomy for motor awareness and motor control.

In everyday life, the successful monitoring of behavior requires continuous updating of the effectiveness of motor acts; one crucial step is becoming aware of the movements one is performing. We studied the anatomical distribution of lesions in right-brain-damaged hemiplegic patients, who obstinately denied their motor impairment, claiming that they could move their paralyzed limbs. Denial was associated with lesions in areas related to the programming of motor acts, particularly Brodmann's premotor areas 6 and 44, motor area 4, and the somatosensory cortex. This association suggests that monitoring systems may be implemented within the same cortical network that is responsible for the primary function that has to be monitored.

Sensorimotor effects on central space representation: prism adaptation influences haptic and visual representations in normal subjects.

Prism adaptation improves visual and haptic manifestations of left neglect, and can induce a small but reliable simulation of left visual neglect in normal individuals. Here, we present two experiments in which the effects of prism adaptation on the representation of space were explored. In Experiment 1, normal subjects were required to locate the centre of a haptically explored circle, before and after adaptation to leftward displacing prisms. In Experiment 2, a visual circle centring task was used. In both tasks, prism adaptation induced a significant rightward shift of performance. In addition, in both experiments, three classical measures of visuo-manual adaptation were taken: the visual shift, the proprioceptive shift and the total shift. The effects found on the haptic and visual tasks did not correlate with any of these measures. This suggests that the effects of prism adaptation on the circle centring tasks did not depend directly on the sensorimotor consequences of the adaptation. These results imply that prism adaptation can affect noetic levels of space representation in normal subjects, supporting the hypothesis that this low-level sensorimotor intervention can exert a bottom-up structuring influence on higher levels of cognitive integration.

Touch-screen system for assessing visuo-motor exploratory skills in neuropsychological disorders of spatial cognition.

A new computerised test adopting touch-screen technology has been developed to assess the visuo-motor exploration of extra-personal space. The test was derived from well-known paper-and-pencil cancellation tasks used widely in the diagnosis and quantitative assessment of unilateral spatial neglect (USN), a neuropsychological syndrome that is more frequent and severe after damage to the right cerebral hemisphere. A main component deficit of USN is the defective visuo-motor exploration of the side of space contralateral to the side of the lesion (contralesional), namely, in right-sided brain-damaged patients it occurs on the left side and vice versa. The computer-based paradigm consisted of a visuo-motor spatial exploratory task: the subjects were instructed to touch, in any order they wished, all the targets they detected on a computer touch-screen. This measured the time of occurrence and the spatial co-ordinates of each touch event and forwarded the data to the computer for storage; the computer provided feedback to the subject by 'tagging' the touched target. The paradigm allowed the calculation of accuracy and latency indexes and recorded the exploratory pathway taken by each subject. A pilot study was performed in ten normal subjects and 15 brain-damaged patients, with and without psychometric evidence of USN; the results showed that the equipment was able to provide quantitative indexes related to the spatial-temporal aspects of exploratory ability, which are useful for diagnostic purposes, and revealed significant differences between the controls and patients with USN: the overall average values of latency and crossing indexes increased in patients with USN, compared with the controls (latency from 0.77 to 1.90s; path crossing index from 7.0% to 59.5%), and the significantly negative USN patient latency gradient (-2.79 against a null control value) evidenced a worsening of performance towards the left side.

Understanding metaphors and idioms: a single-case neuropsychological study in a person with Down syndrome.

The ability of subject F.F., diagnosed with Down syndrome, to appreciate nonliteral (interpreting metaphors and idioms) and literal (vocabulary knowledge, including highly specific and unusual items) aspects of language was investigated. F.F. was impaired in understanding both metaphors and idioms, while her phonological, syntactic and lexical-semantic skills were largely preserved. By contrast, some aspects of F.F.'s executive functions and many visuospatial abilities were defective. The suggestion is made that the interpretation of metaphors and idioms is largely independent of that of literal language, preserved in F.F., and that some executive aspects of working memory and visuospatial and imagery processes may play a role.

Cerebral representations for egocentric space: Functional-anatomical evidence from caloric vestibular stimulation and neck vibration.

The internal representation of space involves the integration of different sensory inputs-visual, somatosensory/proprioceptive, vestibular-yielding reference frames which are not based on individual peripheral sensory codes, being organized instead in ego-centred (e.g. head, trunk, arm) and object- or environment-centred coordinates. Lateralized or direction-specific stimulation of peripheral sensory systems, such as caloric vestibular stimulation (CVS), posterior neck muscle mechanical vibration (NV) and optokinetic stimulation, can induce a distortion of egocentric coordinates, causing, for example, a deviation of the subjective straight ahead in pointing tasks. Appropriate forms of this stimulation can also temporarily improve a variety of pathological manifestations of unilateral neglect. We used PET measurements of regional cerebral blood flow changes in normal volunteers to measure the brain responses shared by CVS and NV. We show that somatosensory areas of the perisylvian cortex including the insula and retroinsular cortex, the temporoparietal junction and somatosensory area II receive signals from both sensory channels. We propose that these anatomical sites contribute to egocentric representation of space.

Extrapersonal visual unilateral spatial neglect and its neuroanatomy.

The neural correlates of left extrapersonal visual unilateral spatial neglect (VUSN), the more extensively investigated component of the neglect syndrome, are reviewed. Damage to a number of right-hemisphere regions brings about VUSN: the posterior parietal cortex (inferior parietal lobule) and, although less frequently, the premotor cortex and subcortical structures, such as the thalamus and the basal ganglia, and white matter fiber tracts. In recent years, a number of studies have investigated the possible association of specific components of left VUSN with damage to specific brain regions within the right hemisphere. The putative distinction most extensively investigated from an anatomical perspective concerns the perceptual vs premotor components of VUSN. In addition, a fine-grain componential analysis of the behavioral tasks used to investigate VUSN is providing more specific insight into the pathological mechanisms underlying the variety of its manifestations. The emerging pattern is that USN is a multifarious disorder, in which specific deficits are associated with damage localized in discrete brain regions and neural circuits. These data concur with evidence from other domains (functional neuroimaging, neurophysiology) to suggest a highly multicomponential neural and functional architecture of spatial cognition.

The neural basis of egocentric and allocentric coding of space in humans: a functional magnetic resonance study.

The spatial location of an object can be represented in the brain with respect to different classes of reference frames, either relative to or independent of the subject's position. We used functional magnetic resonance imaging to identify regions of the healthy human brain subserving mainly egocentric or allocentric (object-based) coordinates by asking subjects to judge the location of a visual stimulus with respect to either their body or an object. A color-judgement task, matched for stimuli, difficulty, motor and oculomotor responses, was used as a control. We identified a bilateral, though mainly right-hemisphere based, fronto-parietal network involved in egocentric processing. A subset of these regions, including a much less extensive unilateral, right fronto-parietal network, was found to be active during object-based processing. The right-hemisphere lateralization and the partial superposition of the egocentric and the object-based networks is discussed in the light of neuropsychological findings in brain-damaged patients with unilateral spatial neglect and of neurophysiological studies in the monkey.

Processing of illusion of length in spatial hemineglect: a study of line bisection.

Bisection of horizontal lines and of the Brentano form of the Müller-Lyer illusion was investigated in six right brain-damaged patients with left spatial hemineglect, and in six control subjects. Patients bisected the lines to the right of the objective mid-point. Comparable illusory effects on line bisection were however found in both patients and control subjects. Relative to the baseline condition, in both groups the subjective midpoint was displaced towards the side expanded by the illusion, both leftwards and rightwards. By contrast, line length and spatial position of the stimulus had differential effects. In neglect patients, the rightward bisection error increased disproportionately with line length, and when the stimulus was located in the left, neglected, side of egocentric space. Control subjects showed no such effects. The suggestion is made that the visual, non-egocentric, processes underlying these illusory effects of length may be spared in patients with left spatial neglect. The possible neural basis of this dissociation is discussed.

A fronto-parietal system for computing the egocentric spatial frame of reference in humans.

Spatial orientation is based on coordinates referring to the subject's body. A fundamental principle is the mid-sagittal plane, which divides the body and space into the left and right sides. Its neural bases were investigated by functional magnetic resonance imaging (fMRI). Seven normal subjects pressed a button when a vertical bar, moving horizontally, crossed the subjective mid-sagittal plane. In the control condition, the subjects' task was to press a button when the direction of the bar movement changed, at the end of each leftward or rightward movement. The task involving the computation of the mid-sagittal plane yielded increased signal in posterior parietal and lateral frontal premotor regions, with a more extensive activation in the right cerebral hemisphere. This direct evidence in normal human subjects that a bilateral, mainly right hemisphere-based, cortical network is active during the computation of the egocentric reference is consistent with neuropsychological studies in patients with unilateral cerebral lesions. Damage to the right hemisphere, more frequently to the posterior-inferior parietal region, may bring about a neglect syndrome of the contralesional, left side of space, including a major rightward displacement of the subjective mid-sagittal plane. The existence of a posterior parietal-lateral premotor frontal network concerned with egocentric spatial reference frames is also in line with neurophysiological studies in the monkey.

Recovery of neglect after right hemispheric damage: H2(15)O positron emission tomographic activation study.

BACKGROUND: The neural correlates of recovery of unilateral neglect (ULN), as well as of other consequences of focal brain damage, are largely unknown. Functional neuroimaging methods (in particular, positron emission tomography [PET]) can be applied to the in vivo study of recovery mechanisms in neurologic patients. OBJECTIVE: To evaluate the functional cerebral correlates of recovery from ULN in patients with right-sided lesions, with the use of a PET activation paradigm. METHODS: Study of 3 patients with cerebrovascular lesions that involved corticosubcortical (patient 1) or subcortical (patients 2 and 3) areas of the right hemisphere. Unilateral neglect was tested twice, before and after completion of a 2-month rehabilitation program, after which all 3 patients showed considerable improvement. Similarly, 2 PET examinations were performed, before and after recovery, during the performance of a visuospatial task requiring the patients to detect and respond to visual targets moving on a computer screen from the right to the left visual hemifield (experimental condition). The cerebral activation was compared with a baseline task in which subjects responded to a black dot flashing in a fixed position of the right hemifield. RESULTS: The brain areas activated by the performance of the visuospatial task before and after recovery were compared. In all 3 patients, the regions notably more active after recovery were almost exclusively found in right-sided cortical areas and largely overlapped with those observed in a group of 4 normal subjects performing the same task. Other areas, which have been shown to be involved in attentional and oculomotor tasks in other PET studies, were also activated in patients with ULN. CONCLUSIONS: The behavioral recovery of ULN in these patients with predominantly subcortical lesions is mainly associated with cerebral activations in cortical regions similar to those observed in normal subjects. There is some evidence of functional reorganization in individual subjects, which involves other areas related to space representation and exploration.

Spatial hemineglect in humans.

The term `spatial hemineglect' refers collectively to disorders of spatial cognition, which concern specific sectors of space with reference to a given coordinate system. Patients with cerebral lesions involving the posterior-inferior parietal and the premotor cortex, most often in the right hemisphere, sometimes fail to explore the extra-personal and personal sectors of space contralateral to the side of the lesion, are not aware of stimuli presented in these portions of space, or of contralateral body parts and their disordered function. In addition to these negative signs patients may also show positive pathological manifestations, such as avoidance or withdrawal from the contralateral side of space, and delusional views concerning contralateral body parts. The many varieties of this disorder can occur in dissociated forms, suggesting a multifaceted organization of the internal representation of space, of spatial attention, and of their neural correlates. Many manifestations of hemineglect are modulated in a similar fashion by specific sensory stimulation that also affects visuo-motor processes in normal subjects. This ongoing sensory modulation might update the internal representations of space in a continuously changing environment, and contribute to the formation, around the vertical orientation of gravity, of our subjective unitary experience of space.

Motor deficits and optokinetic stimulation in patients with left hemineglect.

Optokinetic stimulation with left direction of the movement of luminous dots temporarily improved motor weakness of the left hand in two right-brain-damaged patients with left spatial hemineglect. Stimulation to the right had no effect. In two left-brain-damaged patients, optokinetic stimulation did not affect the right motor weakness, regardless of direction of the movement of the optokinetic stimuli. We suggest that in patients with left hemineglect, contralesional motor deficits have a neglect-related component, which, as other aspects of the neglect syndrome, may be improved by optokinetic stimulation. The mechanisms may include a temporary restoration of the spatial coordinates of bodily representations, pathologically distorted towards the side of the lesion.