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Stroke is the largest cause of complex disability in adults. Approximately half of right-hemisphere stroke survivors suffer spatial neglect–an inability to voluntarily orient to people or objects in contralesional space. Neglect is a significant impediment to successful community reintegration. Prism adaptation (PA) is a promising behavioural intervention that can alleviate symptoms of spatial neglect. PA induces a leftward pointing bias–the prism after-effect (AE). In neglect, the prism AE generalises to improve other sensory, motor, and cognitive domains. Although the formation of an AE is a key index in neglect, we do not yet know where it is formed in the brain. Here, we used a novel computational fMRI-based approach to study, for the first time, the brain circuits that mediate the formation of PA in stroke survivors and age matched controls. Healthy individuals (n = 17) and stroke patients (n = 11) performed prism adaptation during fMRI. Temporal signatures of memory formation were extracted from the behavioural data using a state-space model and regressed against the fMRI data. This revealed that, in both groups, fMRI signal in left sensorimotor cortex correlated with the gradual formation of the prism after-effect during adaptation. This indicates that the sensorimotor cortex may be a useful target for neuromodulation that aims to improve the persistence of therapeutic prism after effects.

Background: Human visual cortical area hMT+, like its homolog MT in the macaque monkey, has been shown to be particularly selective to visual motion. After damage to the primary visual cortex (V1), patients often exhibit preserved ability to detect moving stimuli, which is associated with neural activity in area hMT+. As an anatomical substrate that underlies residual function in the absence of V1, promoting functional plasticity within hMT+ could potentially boost visual performance despite primary visual cortical damage. Objective: To establish in healthy participants whether it is possible to use transcranial direct current stimulation (tDCS) over hMT+ to potentiate learning of visual motion direction discrimination. Methods: Twenty-one participants were trained daily for 5 days on a visual motion direction discrimination task. Task difficulty was increased as performance improved, by decreasing the proportion of coherently moving dots, such that participants were always performing at psychophysical threshold. tDCS, either anodal or sham, was applied daily during 20 min of training. Task performance was assessed at baseline and at the end of the training period. Performance was also compared with a third group of 10 participants from an earlier study who had undergone the same procedures but without tDCS. Results: All participants showed improved task performance both during and after training. Contrary to our hypothesis, anodal tDCS did not further improve performance compared to sham stimulation or no stimulation. Bayesian statistics indicated weak evidence in favor of the null hypothesis. Conclusion: This study found no evidence for a robust effect of anodal tDCS over hMT+ on visual motion direction discrimination learning in the young healthy visual system, although more subtle effects may have been missed in the relatively small sample size.

BackgroundHuman visual cortical area hMT+, like its homologue MT in the macaque monkey, has been shown to be particularly selective to visual motion. After damage to the primary visual cortex (V1), patients often exhibit preserved ability to detect moving stimuli, which is associated with neural activity in area hMT+. As an anatomical substrate underlying residual function in the absence of V1, promoting functional plasticity in hMT+ could potentially boost visual performance despite cortical damage.ObjectiveTo establish in healthy participants whether it is possible to use transcranial direct current stimulation (tDCS) over hMT+ to potentiate learning of visual motion direction discrimination.MethodsParticipants were trained daily for five days on a visual motion direction discrimination task. Task difficulty was increased as performance improved, by decreasing the proportion of coherently moving dots, such that participants were always performing at psychophysical threshold. tDCS, either anodal or sham, was applied daily during the 20-minute training session. Task performance was assessed at baseline and at the end of the training period.ResultsAll participants showed improved task performance both during and after training. Contrary to our hypothesis, anodal tDCS did not further improve performance compared to sham stimulation. Bayesian statistics indicated significant evidence in favour of the null hypothesis.ConclusionAnodal tDCS to hMT+ does not enhance visual motion direction discrimination learning in the young healthy visual system.

Background Negative attention biases are thought to be a causal factor in the development and maintenance of depression. It has been proposed that this bias may be caused by a belief that negative events are more informative than positive events. In the present study, it was investigated whether transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, could modulate information content estimates for rewarding and aversive outcomes in healthy adults [1] , [2] . Methodology Forty healthy volunteers aged 18–45 participated in one sham and one active tDCS session in randomised order. During each session, participants completed an information bias learning task (IBLT) while receiving tDCS targeting bilateral dorsolateral prefrontal cortex (DLPFC) for 20 minutes at 2 mA. Information content estimates for positive and negative outcomes were reflected in participants’ learning rates on the IBLT, which were derived from the data with the use of computational models. Results Active bifrontal tDCS was associated with an increase in learning rates for positive but not negative outcomes on the IBLT (F = 5.47, P Conclusion These findings provide the first experimental evidence that modulating activity in the DLPFC can enhance learning from positive stimuli in healthy adults. This change in learning rates suggests an alteration in participants’ beliefs of how informative positive outcomes are compared to negative outcomes. Additional research is needed to assess whether this effect of tDCS can be harnessed to ameliorate negative attention biases associated with psychiatric disorders. The present results provide an exciting early step in the development of novel interventions for depression.

Contains fulltext : 190289.pdf (Publisher’s version ) (Open Access) Motivational, cognitive and action goals are processed by distinct, topographically organized, corticostriatal circuits. We aimed to test whether processing in the striatum is under causal control by cortical regions in the human brain by investigating the effects of offline transcranial magnetic stimulation (TMS) over distinct frontal regions associated with motivational, cognitive and action goal processing. Using a three-session counterbalanced within-subject crossover design, continuous theta burst stimulation was applied over the anterior prefrontal cortex (aPFC), dorsolateral prefrontal cortex, or premotor cortex, immediately after which participants (N = 27) performed a paradigm assessing reward anticipation (motivation), task (cognitive) switching, and response (action) switching. Using task-related functional magnetic resonance imaging (fMRI), we assessed the effects of stimulation on processing in distinct regions of the striatum. To account for non-specific effects, each session consisted of a baseline (no-TMS) and a stimulation (post-TMS) fMRI run. Stimulation of the aPFC tended to decrease reward-related processing in the caudate nucleus, while stimulation of the other sites was unsuccessful. A follow-up analysis revealed that aPFC stimulation also decreased processing in the putamen as a function of the interaction between all factors (reward, cognition and action), suggesting stimulation modulated the transfer of motivational information to cortico-striatal circuitry associated with action control.

BackgroundHighly co-morbid mood and anxiety disorders are associated with aberrant fronto-limbic signalling during emotional processing. Animal models suggest that hypoactive prefrontal cortex weakens top-down control of limbic structures, causing heightened limbic and behavioural reactivity to negative information. Here we tested for this causal mechanism in human trait anxiety. We reasoned that if dorsolateral prefrontal cortex controls amygdala response to affective information, then stimulation of that brain region should reduce the hyperactive amygdala threat responsivity seen in trait anxiety.MethodsUsing a within-subjects design, sixteen high-trait anxious females received active and sham transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex, in counterbalanced order, with sessions timed to be at least one month apart. Each session was followed immediately by a functional magnetic resonance imaging (fMRI) scan during which participants performed an attentional task with threat-related distractors.ResultsAs predicted, compared to sham stimulation, active prefrontal cortex stimulation reduced amygdala threat reactivity and simultaneously increased activity in cortical regions associated with attentional control and improved task accuracy.ConclusionsThese results demonstrate a causal role for impoverished frontal regulation of amygdaloid function in attentional capture by threat in trait anxiety. The finding that prefrontal stimulation reduces amygdala threat reactivity acutely indicates a neurocognitive mechanism that could contribute to tDCS treatment effects in affective disorders.

Prism adaptation induces rapid recalibration of visuomotor coordination. The neural mechanisms of prism adaptation have come under scrutiny since the observations that the technique can alleviate hemispatial neglect following stroke, and can alter spatial cognition in healthy controls. Relative to non-imaging behavioral studies, fMRI investigations of prism adaptation face several challenges arising from the confined physical environment of the scanner and the supine position of the participants. Any researcher who wishes to administer prism adaptation in an fMRI environment must adjust their procedures enough to enable the experiment to be performed, but not so much that the behavioral task departs too much from true prism adaptation. Furthermore, the specific temporal dynamics of behavioral components of prism adaptation present additional challenges for measuring their neural correlates. We developed a system for measuring the key features of prism adaptation behavior within an fMRI environment. To validate our configuration, we present behavioral (pointing) and head movement data from 11 right-hemisphere lesioned patients and 17 older controls who underwent sham and real prism adaptation in an MRI scanner. Most participants could adapt to prismatic displacement with minimal head movements, and the procedure was well tolerated. We propose recommendations for fMRI studies of prism adaptation based on the design-specific constraints and our results.

“Priming of pop-out” is a form of implicit memory that facilitates detection of a recently inspected search target. Repeated presentation of a target's features or its spatial position improves detection speed (feature/spatial priming). This study investigated a role for the human frontal eye fields (FEFs) in the priming of color pop-out. To test the hypothesis that the FEFs play a role in short-term memory storage, transcranial magnetic stimulation (TMS) was applied during the intertrial interval. There was no effect of TMS on either spatial or feature priming. To test whether the FEFs are important when a saccade is being programmed to a repeated target color or location, TMS was applied during the search array. TMS over the left but not the right FEFs abolished spatial priming, but had no effect on feature priming. These findings demonstrate functional specialization of the left FEFs for spatial priming, and distinguish this role from target discrimination and saccade-related processes. The results suggest that the left FEFs integrate a spatial memory signal with an evolving saccade program, which facilitates saccades to a recently inspected location.

Transcranial direct current stimulation (TDCS) of primary motor cortex (M1) can transiently improve paretic hand function in chronic stroke. However, responses are variable so there is incentive to try to improve efficacy and or to predict response in individual patients. Both excitatory (Anodal) stimulation of ipsilesional M1 and inhibitory (Cathodal) stimulation of contralesional M1 can speed simple reaction time. Here we tested whether combining these two effects simultaneously, by using a bilateral M1–M1 electrode montage, would improve efficacy. We tested the physiological efficacy of Bilateral, Anodal or Cathodal TDCS in changing motor evoked potentials (MEPs) in the healthy brain and their behavioural efficacy in changing reaction times with the paretic hand in chronic stroke. In addition, we aimed to identify clinical or neurochemical predictors of patients' behavioural response to TDCS. There were three main findings: 1) unlike Anodal and Cathodal TDCS, Bilateral M1–M1 TDCS (1 mA, 20 min) had no significant effect on MEPs in the healthy brain or on reaction time with the paretic hand in chronic stroke patients; 2) GABA levels in ipsilesional M1 predicted patients' behavioural gains from Anodal TDCS; and 3) although patients were in the chronic phase, time since stroke (and its combination with Fugl–Meyer score) was a positive predictor of behavioural gain from Cathodal TDCS. These findings indicate the superiority of Anodal or Cathodal over Bilateral TDCS in changing motor cortico-spinal excitability in the healthy brain and in speeding reaction time in chronic stroke. The identified clinical and neurochemical markers of behavioural response should help to inform the optimization of TDCS delivery and to predict patient outcome variability in future TDCS intervention studies in chronic motor stroke., Highlights • Ipsilesional M1 GABA levels predict motor gains from Anodal TDCS in chronic stroke. • Time since stroke and Fugl–Meyer score jointly predict response to Cathodal TDCS. • Bilateral motor cortex TDCS did not reliably change motor evoked potentials. • Bilateral motor cortex TDCS did not reliably change manual reaction time.

Unilateral neglect is a disabling syndrome frequently observed following right hemisphere brain damage. Symptoms range from visuo-motor impairments through to deficient visuo-spatial imagery, but impairment can also affect the auditory modality. A short period of adaptation to a rightward prismatic shift of the visual field is known to improve a wide range of hemispatial neglect symptoms, including visuo-manual tasks, mental imagery, postural imbalance, visuo-verbal measures and number bisection. The aim of the present study was to assess whether the beneficial effects of prism adaptation may generalize to auditory manifestations of neglect. Auditory extinction, whose clinical manifestations are independent of the sensory modalities engaged in visuo-manual adaptation, was examined in neglect patients before and after prism adaptation. Two separate groups of neglect patients (all of whom exhibited left auditory extinction) underwent prism adaptation: one group (n = 6) received a classical prism treatment ('Prism' group), the other group (n = 6) was submitted to the same procedure, but wore neutral glasses creating no optical shift (placebo 'Control' group). Auditory extinction was assessed by means of a dichotic listening task performed three times: prior to prism exposure (pre-test), upon prism removal (0 h post-test) and 2 h later (2 h post-test). The total number of correct responses, the lateralization index (detection asymmetry between the two ears) and the number of left-right fusion errors were analysed. Our results demonstrate that prism adaptation can improve left auditory extinction, thus revealing transfer of benefit to a sensory modality that is orthogonal to the visual, proprioceptive and motor modalities directly implicated in the visuo-motor adaptive process. The observed benefit was specific to the detection asymmetry between the two ears and did not affect the total number of responses. This indicates a specific effect of prism adaptation on lateralized processes rather than on general arousal. Our results suggest that the effects of prism adaptation can extend to unexposed sensory systems. The bottom-up approach of visuo-motor adaptation appears to interact with higher order brain functions related to multisensory integration and can have beneficial effects on sensory processing in different modalities. These findings should stimulate the development of therapeutic approaches aimed at bypassing the affected sensory processing modality by adapting other sensory modalities. © The Author 2010.

Contains fulltext : 110704.pdf (Publisher’s version ) (Open Access) Cognitive flexibility is known to depend on the striatum. However, the striatum does not act in isolation to bias cognitive flexibility. In particular, cognitive flexibility also implicates the frontal cortex. Here we tested the hypothesis that the human frontal cortex controls cognitive flexibility by regulating striatal function via topographically specific frontostriatal connections. To this end, we exploited a repetitive transcranial magnetic stimulation (TMS) protocol over frontal cortex that is known to increase dopamine release in the striatum. This intervention was combined with functional magnetic resonance imaging to determine the functional and topographic specificity of its consequences at the whole brain level. Participants were scanned both before and after off-line TMS while performing a cognitive switching task that is known to depend on a specific striatal substructure, the putamen. Frontal stimulation perturbed task-specific functional signals in the putamen, while reducing fronto-striatal functional connectivity. There were no such effects of TMS over the medial parietal cortex. These data strengthen the hypothesis that cognitive flexibility involves topographic frontal control of striatal function.

A large proportion of right-hemisphere stroke patients exhibit unilateral neglect, a neurological condition characterised by deficits for perceiving, attending, representing, and/or performing actions within their left-sided space. Unilateral neglect is responsible for many debilitating effects on everyday life, for poor functional recovery, and for decreased ability to benefit from treatment. Prism adaptation (PA) to a right lateral displacement of the visual field (induced by a simple target-pointing task with base-left wedge prisms) is known to directionally bias visuo-motor and sensory-motor correspondences and has recently been found to improve various symptoms of neglect. For example, performance on classical pen-and-pencil visuo-motor tests could be improved for at least two hours after adaptation. Effects of PA have also been described for non-motor and non-visual tasks, such as for somatosensory extinction, for deficits in mental imagery of geographic maps and in number bisection, and even for visuo-constructive disorders. These results suggest that the effects of prism adaptation can extend to unexposed sensory systems. The bottom-up approach of visuo-motor adaptation appears to interact with higher order brain functions related to multisensory integration and can have beneficial effects on sensory processing in different modalities. Lesion studies and functional imaging data point to a cerebello-cortical network in which each structure plays a specific role, though not necessarily one that is crucial for adaptation. Prism adaptation could act specifically not only on the ipsilesional bias characteristic of hemineglect but rehabilitates more generally the other spatial cognition deficits due to damage of the right hemisphere.

Transcranial direct current stimulation (tDCS) is currently attracting increasing interest as a tool for neurorehabilitation. However, local and distant effects of tDCS on motor-related cortical activation patterns remain poorly defined, limiting the rationale for its use. Here we describe the results of a functional magnetic resonance imaging (MRI) experiment designed to characterize local and distant effects on cortical motor activity following excitatory anodal stimulation and inhibitory cathodal stimulation. Fifteen right-handed subjects performed a visually cued serial reaction time task with their right hand in a 3-T MRI scanner both before and after 10 min of 1-mA tDCS applied to the left primary motor cortex (M1). Relative to sham stimulation, anodal tDCS led to short-lived activation increases in the M1 and the supplementary motor area (SMA) within the stimulated hemisphere. The increase in activation in the SMA with anodal stimulation was found also when directly comparing anodal with cathodal stimulation. Relative to sham stimulation, cathodal tDCS led to an increase in activation in the contralateral M1 and dorsal premotor cortex (PMd), as well as an increase in functional connectivity between these areas and the stimulated left M1. These increases were also found when directly comparing cathodal with anodal stimulation. Significant within-session linear decreases in activation occurred in all scan sessions. The after-effects of anodal tDCS arose primarily from a change in the slope of these decreases. In addition, following sham stimulation compared with baseline, a between-session decrease in task-related activity was found. The effects of cathodal tDCS arose primarily from a reduction of this normal decrease.

Functional connections between dorsal premotor cortex (PMd) and primary motor cortex (M1) have been revealed by paired-pulse transcranial magnetic stimulation (TMS). We tested if such connections would be modulated during a cognitive process (response selection) known to rely on those circuits. PMd-M1 TMS applied 75 ms after a cue to select a manual response facilitated motor-evoked potentials (MEPs). MEPs were facilitated at 50 ms in a control task of response execution, suggesting that PMd-M1 interactions at 75 ms are functionally specific to the process of response selection. At 100 ms, PMd-M1 TMS delayed choice reaction time (RT). Importantly, the MEP (at 75 ms) and the RT (at 100 ms) effects were correlated in a way that was hand-specific. When the response was made with the M1-contralateral hand, MEPs correlated with slower RTs. When the response was made with the M1-ipsilateral hand, MEPs correlated with faster RTs. Paired-pulse TMS confined to M1 did not produce these effects, confirming the causal influence of PMd inputs. This study shows that a response selection signal evolves in PMd early during the reaction period (75-100 ms), impacts on M1 and affects behaviour. Such interactions are temporally, anatomically and functionally specific, and have a causal role in choosing which movement to make.

Successful search for a target in a visual scene requires many cognitive operations, including orienting, detecting the target, and rejecting distractors. Performance in search is affected by a number of factors, including the number of targets and distractors, their similarity, motion in the display, location, and viewing history of the stimuli, etc. A task with so many stimulus variables and behavioural or neural responses may require different brain areas to interact in ways that depend on specific task demands. Until recently the right posterior parietal cortex has been ascribed a pre-eminent role in visual search. Based on recent physiological and brain imaging evidence, and on a programme of magnetic stimulation studies designed to compare directly the contributions of the parietal cortex and the human frontal eye fields in search, we have generated an account of similarities and differences between these two brain regions. The comparison suggests that the frontal eye fields are important for some aspects of search previously attributed to the parietal cortex, and that accounts of the cortical contributions to search need to be reassessed in the light of these findings. © 2006 Psychology Press Ltd.

Theoretical models of visual neglect and extinction entail claims about the normal functioning of attention and parietal cortex in the healthy brain: (1) ‘pseudoneglect’, a commonly observed attentional bias towards left space, reflects the greater dominance of parietal cortex activity of the right versus left hemisphere; (2) the capacity to distribute attention bilaterally depends causally on the relative balance of parietal activity between the hemispheres; (3) disruption of the dominant right parietal cortex shifts this inter-hemispheric balance leftward, causing a rightward shift in attentional bias. We tested these claims using low-frequency offline transcranial magnetic stimulation (TMS) to transiently inhibit activity in the right angular gyrus/intra-parietal sulcus, followed by a visual detection task to assess changes in attentional bias, and functional magnetic resonance imaging (fMRI) to test for the predicted leftward shift in brain activity. The task required participants to covertly monitor both hemifields to detect and report the location of upcoming transient visual targets that appeared on the left, right or bilaterally. In the behavioural experiment, participants exhibited a leftward attentional bias (‘pseudoneglect’) at baseline, which was abolished by TMS. In the fMRI experiment, participants activated an expected network of visual, parietal and frontal cortex bilaterally during the period of covert bilateral attention. TMS shifted the relative hemispheric balance of parietal activity from right to left. The consistent direction of TMS-induced behavioural and functional change indicates a causal role for parietal inter-hemispheric balance in distributing visual attention across space.

Contains fulltext : 140033.pdf (Publisher’s version ) (Open Access) Covertly directing visuospatial attention produces a frequency-specific modulation of neuronal oscillations in occipital and parietal cortices: anticipatory alpha (8-12 Hz) power decreases contralateral and increases ipsilateral to attention, whereas stimulus-induced gamma (>40 Hz) power is boosted contralaterally and attenuated ipsilaterally. These modulations must be under top-down control; however, the control mechanisms are not yet fully understood. Here we investigated the causal contribution of the human frontal eye field (FEF) by combining repetitive transcranial magnetic stimulation (TMS) with subsequent magnetoencephalography. Following inhibitory theta burst stimulation to the left FEF, right FEF, or vertex, participants performed a visual discrimination task requiring covert attention to either visual hemifield. Both left and right FEF TMS caused marked attenuation of alpha modulation in the occipitoparietal cortex. Notably, alpha modulation was consistently reduced in the hemisphere contralateral to stimulation, leaving the ipsilateral hemisphere relatively unaffected. Additionally, right FEF TMS enhanced gamma modulation in left visual cortex. Behaviorally, TMS caused a relative slowing of response times to targets contralateral to stimulation during the early task period. Our results suggest that left and right FEF are causally involved in the attentional top-down control of anticipatory alpha power in the contralateral visual system, whereas a right-hemispheric dominance seems to exist for control of stimulus-induced gamma power. These findings contrast the assumption of primarily intrahemispheric connectivity between FEF and parietal cortex, emphasizing the relevance of interhemispheric interactions. The contralaterality of effects may result from a transient functional reorganization of the dorsal attention network after inhibition of either FEF. 10 p.

Introduction Prism adaptation is a form of sensorimotor learning where participants have to regain normal pointing accuracy under circumstances where their entire visual field is shifted to one side by prism glasses. Once the goggles are removed, prism aftereffects are expressed as pointing errors in the direction opposite to that of the prismatic shift. When coupled with prism adaptation, anodal transcranial direct current stimulation (a-tDCS) to the primary motor cortex (M1) increases retention of prism aftereffects in healthy participants. However, the mechanisms by which this motor memory boost occurs remain largely unknown. Objectives We sought to investigate the brain mechanisms underlying stimulation-enhanced motor memory by examining how inter-individual differences in neurochemical and functional response to a-tDCS relate to inter-individual differences in its effect on prism aftereffects. Materials and methods Participants underwent two MR scanning sessions during which they either received sham or real a-tDCS to M1. We used Magnetic Resonance Spectroscopy (MRS) and resting state functional Magnetic Resonance Imaging (rs-fMRI) to characterise individuals’ neurochemical and functional response to a-tDCS ( Bachtiar et al., 2015 , Stagg et al., 2009 ). Participants also underwent two behavioural sessions during which prism adaptation was either combined with sham or real a-tDCS. Results Preliminary results suggest that the bigger the reduction in GABA concentration in M1 following a-tDCS, the stronger the effect of a-tDCS on the retention of prism aftereffects. Conclusion This result supports the idea that the effect of anodal tDCS on motor memory depends on its effect on the GABAergic system. Further analyses will also consider the influence of the a-tDCS induced changes in functional connectivity within the motor network.

Background The difficulty in treating mood disorders has brought about clinical interest in alternative treatments, such as transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). However, the optimal parameters for stimulation and underlying mechanisms of action are unclear. Psychiatric treatments have acute effects on emotional processing that predict later therapeutic action. Such effects have been proposed as cognitive biomarkers for screening novel treatments for depression and anxiety. Methods This study assessed the effect of tDCS on a battery of emotional processing measures sensitive to antidepressant action. To refine optimal stimulation parameters, DLPFC stimulation using two common electrode montages was compared with sham. Sixty healthy volunteers received 20 minutes of active or sham DLPFC stimulation before completing computerized emotional processing tasks, including a dot-probe measure of vigilance to threat. Results Relative to sham stimulation, participants receiving simultaneous anodal stimulation of left DLPFC and cathodal stimulation of right DLPFC (bipolar-balanced montage) showed reduced vigilance to threatening stimuli. There was no such significant effect when the cathode was placed on the supraorbital ridge (bipolar-unbalanced montage). There were no effects of tDCS on other measures of emotional processing. Conclusions Our findings provide the first experimental evidence that modulating activity in the DLPFC reduces vigilance to threatening stimuli. This significant reduction in fear vigilance is similar to that seen with anxiolytic treatments in the same cognitive paradigm. The finding that DLPFC tDCS acutely alters the processing of threatening information suggests a potential cognitive mechanism that could underwrite treatment effects in clinical populations.

It has been proposed that motor adaptation depends on at least two learning systems, one that learns fast but with poor retention and another that learns slowly but with better retention (Smith MA, Ghazizadeh A, Shadmehr R. PLoS Biol 4: e179, 2006). This two-state model has been shown to account for a range of behavior in the force field adaptation task. In the present study, we examined whether such a two-state model could also account for behavior arising from adaptation to a prismatic displacement of the visual field. We first confirmed that an “adaptation rebound,” a critical prediction of the two-state model, occurred when visual feedback was deprived after an adaptation-extinction episode. We then examined the speed of decay of the prism aftereffect (without any visual feedback) after repetitions of 30, 150, and 500 trials of prism exposure. The speed of decay decreased with the number of exposure trials, a phenomenon that was best explained by assuming an “ultraslow” system, in addition to the fast and slow systems. Finally, we compared retention of aftereffects 24 h after 150 or 500 trials of exposure: retention was significantly greater after 500 than 150 trials. This difference in retention could not be explained by the two-state model but was well explained by the three-state model as arising from the difference in the amount of adaptation of the “ultraslow process.” These results suggest that there are not only fast and slow systems but also an ultraslow learning system in prism adaptation that is activated by prolonged prism exposure of 150–500 trials.

We investigated the contributions of the cerebellum and the motor cortex (M1) to acquisition and retention of human motor memories in a force field reaching task. We found that anodal transcranial direct current stimulation (tDCS) of the cerebellum, a technique that is thought to increase neuronal excitability, increased the ability to learn from error and form an internal model of the field, while cathodal cerebellar stimulation reduced this error-dependent learning. In addition, cathodal cerebellar stimulation disrupted the ability to respond to error within a reaching movement, reducing the gain of the sensory-motor feedback loop. By contrast, anodal M1 stimulation had no significant effects on these variables. During sham stimulation, early in training the acquired motor memory exhibited rapid decay in error-clamp trials. With further training the rate of decay decreased, suggesting that with training the motor memory was transformed from a labile to a more stable state. Surprisingly, neither cerebellar nor M1 stimulation altered these decay patterns. Participants returned 24 hours later and were re-tested in error-clamp trials without stimulation. The cerebellar group that had learned the task with cathodal stimulation exhibited significantly impaired retention, and retention was not improved by M1 anodal stimulation. In summary, non-invasive cerebellar stimulation resulted in polarity-dependent up- or down-regulation of error-dependent motor learning. In addition, cathodal cerebellar stimulation during acquisition impaired the ability to retain the motor memory overnight. Thus, in the force field task we found a critical role for the cerebellum in both formation of motor memory and its retention.

Unilateral neglect is a neurological condition responsible for many debilitating effects on everyday life, poor functional recovery, and decreased ability to benefit from treatment. Prism adaptation (PA) to a right lateral displacement of the visual field is classically known to directionally bias visuo-motor and sensory-motor correspondences. One longstanding issue about this visuo-motor plasticity is about its specificity to the exposure condition. In contrast to very poor transfer to unexposed effectors classically described in healthy subjects, therapeutic results obtained in neglect patients suggested that PA can generate unexpected "expansion". Prism adaptation affects numerous levels of neglect symptomatology, suggesting that its effects somehow expand to unexposed sensory, motor and cognitive systems. The available body of evidence in support for this expansion raises important questions about the mechanisms involved in producing unexpected cognitive effects following a simple and moderate visuo-motor adaptation. We further develop here the idea that prism adaptation expansion to spatial cognition involves a cerebello-cortical network and review support for this model. Building on the basic, therapeutical and pathophysiological knowledge accumulated over the last 15 years, we also provide guidelines for the optimal use of prism adaptation in the clinic. Although further research and clinical trials are required to precisely define the ideal regime for routine applications, the current state of the art allows us to outline practical recommendations for therapeutical use of prisms.

This article reviews the contribution of transcranial magnetic stimulation (TMS) research to the understanding of attention, eye movements, visual search, and neglect. It considers how TMS studies have confirmed, refined, or challenged prevailing ideas about the neural basis of higher visual cognition. It shows that TMS has enhanced the understanding of the location, timing, and functional roles of visual cognitive processes in the human brain. The main focus is on studies of posterior parietal cortex (PPC), with reference to recent work on the frontal eye fields (FEFs). TMS offers many advantages to complement neuropsychological patient studies to enhance the understanding of how the fronto-parietal cortical nerves function. The visuo-spatial neglect- and extinction-like deficits incurred by parietal damage have been modelled successfully using TMS. Future work might be directed at teasing apart the distinct functional roles of nodes within this frontoparietal network in different sensorimotor contexts.

Adaptation to right-deviating prisms is a promising intervention for the rehabilitation of patients with left spatial neglect. In order to test the lateral specificity of prism adaptation on left neglect, the present study evaluated the effect of left-deviating prism on straight-ahead pointing movements and on several classical neuropsychological tests in a group of five right brain-damaged patients with left spatial neglect. A group of healthy subjects was also included for comparison purposes. After a single session of exposing simple manual pointing to left-deviating prisms, contrary to healthy controls, none of the patients showed a reliable change of the straight-ahead pointing movement in the dark. No significant modification of attentional paper-and-pencil tasks was either observed immediately or 2 hours after prism adaptation. These results suggest that the therapeutic effect of prism adaptation on left spatial neglect relies on a specific lateralized mechanism. Evidence for a directional effect for prism adaptation both in terms of the side of the visuomanual adaptation and therefore possibly in terms of the side of brain affected by the stimulation is discussed.

Transcranial direct current stimulation, a form of non-invasive brain stimulation, is showing increasing promise as an adjunct therapy in rehabilitation following stroke. However, although significant behavioural improvements have been reported in proof-of-principle studies, the underlying mechanisms are poorly understood. The rationale for transcranial direct current stimulation as therapy for stroke is that therapeutic stimulation paradigms increase activity in ipsilesional motor cortical areas, but this has not previously been directly tested for conventional electrode placements. This study was performed to test directly whether increases in ipsilesional cortical activation with transcranial direct current stimulation are associated with behavioural improvements in chronic stroke patients. Patients at least 6 months post-first stroke participated in a behavioural experiment ( n = 13) or a functional magnetic resonance imaging experiment ( n = 11), each investigating the effects of three stimulation conditions in separate sessions: anodal stimulation to the ipsilesional hemisphere; cathodal stimulation to the contralesional hemisphere; and sham stimulation. Anodal (facilitatory) stimulation to the ipsilesional hemisphere led to significant improvements (5–10%) in response times with the affected hand in both experiments. This improvement was associated with an increase in movement-related cortical activity in the stimulated primary motor cortex and functionally interconnected regions. Cathodal (inhibitory) stimulation to the contralesional hemisphere led to a functional improvement only when compared with sham stimulation. We show for the first time that the significant behavioural improvements produced by anodal stimulation to the ipsilesional hemisphere are associated with a functionally relevant increase in activity within the ipsilesional primary motor cortex in patients with a wide range of disabilities following stroke. * Abbreviations : tDCS : transcranial direct current stimulation M1 : primary motor cortex

Coincident pairing of presynaptic and postsynaptic activity selectively strengthens synaptic connections, a key mechanism underlying cortical plasticity. Using paired associative transcranial magnetic stimulation (TMS), we demonstrate selective potentiation of physiological connectivity between two human brain regions, ventral premotor cortex (PMv) and primary motor cortex (M1) after repeated paired-pulse TMS of PMv and M1. The effect was anatomically specific: paired stimulation of the presupplementary motor area and M1 did not induce changes in PMv–M1 pathway connectivity. The effect was dependent on stimulation order: repeated stimulation of PMv before M1 led to strengthening of the PMv–M1 pathway, while repeated stimulation of M1 before PMv diminished the strength of the PMv–M1 pathway. The expression of the change in the pathway depended on the cognitive state of the subject at the time of testing: when the subject was tested at rest, paired PMv–M1 stimulation led to an increased inhibitory influence of PMv over M1, but when the subject was tested while engaged in a visuomotor task, PMv–M1 stimulation led to an increased facilitatory influence of PMv over M1. Plasticity evolved rapidly, lasted for at least 1 h, and began to reverse 3 h after intervention.

A large proportion of right-hemisphere stroke patients exhibits spatial neglect, a neurological condition characterised by deficits for perceiving, attending, representing, and/or performing actions within their left-sided space. spatial neglect is responsible for many debilitating effects on everyday life, for poor functional recovery, and for decreased ability to benefit from treatment. Prism adaptation (PA) to a right lateral displacement of the visual field (induced by a simple target-pointing task while wearing base-left wedge prisms) is known to directionally bias visuo-motor and sensory-motor correspondences and has recently been found to improve various symptoms of neglect. For example, performance on classical pen-and-pencil visuo-motor tests could be improved for at least 2 h following adaptation. Further effects of PA have also been described for non-motor and non-visual tasks, such as for somatosensory extinction or dichotic listening, for deficits in mental imagery of geographic maps and in number bisection, and even for visuo-constructive disorders. These results suggest that the effects of prism adaptation can extend to unexposed sensory systems. The bottom-up approach of visuo-motor adaptation appears to interact with higher order brain functions related to multisensory integration and can have beneficial effects on sensory processing in different modalities. Lesion studies and functional imaging data point to a cerebello-cortical network in which the cerebellum is crucial for adaptation and the cortex is involved in functional gains. Prism adaptation may act not only on the ipsilesional bias characteristic of neglect and also alleviate more generally other spatial cognition deficits due to attentional bias.

We review three ways in which transcranial magnetic stimulation (TMS) has been used to investigate causal interactions between different brain areas: (1) combined with functional imaging; (2) combined with EEG; and (3) applied successively over two brain areas. We discuss the theoretical advantages of each technique, illustrated by examples from the literature, and highlight the potential of these approaches to provide novel insights into the neural bases of action control.

Summary After unilateral stroke, the dorsal premotor cortex (PMd) in the intact hemisphere is often more active during movement of an affected limb. Whether this contributes to motor recovery is unclear. Functional magnetic resonance imaging (fMRI) was used to investigate short-term reorganization in right PMd after transcranial magnetic stimulation (TMS) disrupted the dominant left PMd, which is specialized for action selection. Even when 1 Hz left PMd TMS had no effect on behavior, there was a compensatory increase in activity in right PMd and connected medial premotor areas. This activity was specific to task periods of action selection as opposed to action execution. Compensatory activation changes were both functionally specific and anatomically specific: the same pattern was not seen after TMS of left sensorimotor cortex. Subsequent TMS of the reorganized right PMd did disrupt performance. Thus, this pattern of functional reorganization has a causal role in preserving behavior after neuronal challenge.

Frontal eye field (FEF) neurons discharge in response to behaviorally relevant stimuli that are potential targets for saccades. Distinct visual and motor processes have been dissociated in the FEF of macaque monkeys, but little is known about the visual processing capacity of FEF in humans. We used double-pulse transcranial magnetic stimulation [(d)TMS] to investigate the timing of target discrimination during visual conjunction search. We applied dual TMS pulses separated by 40 msec over the right FEF and vertex. These were applied in five timing conditions to sample separate time windows within the first 200 msec of visual processing. (d)TMS impaired search performance, reflected in reduced d′ scores. This effect was limited to a time window between 40 and 80 msec after search array onset. These parameters correspond with single-cell activity in FEF that predicts monkeys' behavioral reports on hit, miss, false alarm, and correct rejection trials. Our findings demonstrate a crucial early role for human FEF in visual target discrimination that is independent of saccade programming.

Background ‘Neglect’ is a common disabling neurological syndrome after right hemisphere stroke. It is a multifaceted disorder in which patients lose the capacity to voluntarily attend to the left half of space, objects or the body. While spontaneous remission can occur over time, one third of patients suffer chronic neglect and life-long disability. Prism adaptation (PA) is a behavioural intervention in which patients learn to adapt to a rightward optical (prismatic) shift, by re-calibrating their pointing behaviour from the right (intact) into the left (neglected) hemi-space. Following PA, patients exhibit a leftward shift in pointing behaviour, known as a prism after-effect. While this after-effect is present, neglect symptoms are improved (Rossetti et al., 1998 Nature; 395). A few minutes of PA can induce transient gains across a remarkable range of deficits (e.g.: visual search, drawing, postural control, wheelchair driving and reading; Pisella et al., 1996 Restor Neurol Neurosci; 24). However, not all patients respond, and in those who do, repeated interventions are required to produce lasting benefit. Aims Our goal was to devise a brain stimulation protocol that would enhance the efficacy of prism therapy for neglect. Specifically, we aimed to test the hypothesis that a plasticity-promoting protocol would enhance consolidation of prism after-effects, and thus cause lasting improvements in visual neglect. Methods We used a bench-to-bedside translational strategy, devising protocols and testing hypotheses first in healthy controls (N = 52), and then transferring the most promising intervention to patients. In a series of six experiments, we tested the effect of transcranial direct current stimulation (TDCS) to a variety of cortical regions on learning and retention rates for PA. Next, in a series of longitudinal studies in three patients, we tested the impact of the most promising stimulation protocol on performance of a battery of neglect tests. Results The experiments in healthy volunteers enabled us to identify a protocol that enhanced consolidation of prism after-effects over a time-scale of several days, in a manner that was functionally, anatomically and neurochemically specific, as well as cognitive state dependent. When we translated this protocol to patients, we found that a single 20-min intervention significantly improved neglect [relative gain: 66% (patient 1 session 1), 45% (session 2), 53% (patient 2), 25% (patient 3)]. These effects lasted weeks to months and did not return to baseline [duration of benefit: 80 days (patient 1 session 1), 46 days (session 2), 46 days (patient 2), 21 days (patient 3)]. Notably, this occurred in patients with chronic, severe, neglect who showed no response to prism therapy alone. In a single-case double crossover design (patient 1) comparing real versus sham TDCS, the patient exhibited a large positive response to each real TDCS, and the effects accumulated, suggesting that repeated treatments might induce gradual recovery. Conclusions This is the first proof-of-principle demonstration that a single-shot, simple behavioural procedure combined with TDCS can remediate treatment-unresponsive chronic visual neglect. TDCS provoked a positive therapeutic response in patients who did not otherwise respond to the behavioural therapy. By enhancing the consolidation of prism therapy, TDCS increased both the gain and longevity of therapeutic response, yielding large, long-lasting improvements in visual neglect.

Transcranial direct current stimulation (TDCS) of primary motor cortex (M1) can transiently improve paretic hand function in chronic stroke. However, responses are variable so there is incentive to try to improve efficacy or to predict response in individual patients. Both excitatory (Anodal) stimulation of ipsilesional M1 and inhibitory (Cathodal) stimulation of contralesional M1 can speed simple reaction time. Here we tested whether combining these two effects simultaneously, by using a bilateral M1–M1 electrode montage, would improve efficacy. We tested the physiological efficacy of Bilateral, Anodal or Cathodal TDCS in changing motor evoked potentials (MEPs) in the healthy brain and their behavioural efficacy in changing reaction times with the paretic hand in chronic stroke. In addition, we aimed to identify clinical or neurochemical predictors of patients’ behavioural response to TDCS. There were three main findings: (1) Unlike Anodal and Cathodal TDCS, Bilateral M1–M1 TDCS (1 mA, 20 min) had no significant effect on MEPs in the healthy brain or on reaction time with the paretic hand in chronic stroke patients; (2) GABA levels in ipsilesional M1 predicted patients’ behavioural gains from Anodal TDCS; (3) Although patients were in the chronic phase, time since stroke (and its combination with Fugl-Meyer score) was a positive predictor of behavioural gain from Cathodal TDCS. These findings indicate the superiority of Anodal or Cathodal over Bilateral TDCS in changing motor corticospinal excitability in the healthy brain and in speeding reaction time in chronic stroke. The identified clinical and neurochemical markers of behavioural response should help to inform the optimization of TDCS delivery and to predict patient outcome variability in future TDCS intervention studies in chronic motor stroke.