Limb Apraxias: The Influence of Higher Order Perceptual and Semantic Deficits in Motor Recovery After Stroke.

Stroke is a leading cause of disability worldwide. Limb apraxia is a group of higher order motor disorders associated with greater disability and dependence after stroke. Original neuropsychology studies distinguished separate brain pathways involved in perception and action, known as the dual stream hypothesis. This framework has allowed a better understanding of the deficits identified in Limb Apraxia. In this review, we propose a hierarchical organization of this disorder, in which a distinction can be made between several visuomotor pathways that lead to purposeful actions. Based on this, executive apraxias (such as limb kinetic apraxia) cause deficits in executing fine motor hand skills, and intermediate apraxias (such as optic ataxia and tactile apraxia) cause deficits in reaching to grasp and manipulating objects in space. These disorders usually affect the contralesional limb. A further set of disorders collectively known as limb apraxias include deficits in gesture imitation, pantomime, gesture recognition, and object use. These deficits are due to deficits in integrating perceptual and semantic information to generate complex movements. Limb apraxias are usually caused by left-hemisphere lesions in right-handed stroke patients, affecting both limbs. The anterior- to posterior-axis of brain areas are disrupted depending on the increasing involvement of perceptual and semantic processes with each condition. Lower-level executive apraxias are linked to lesions in the frontal lobe and the basal ganglia, while intermediate apraxias are linked to lesions in dorso-dorsal subdivisions of the dorsal fronto-parietal networks. Limb apraxias can be caused by lesions in both dorsal and ventral subdivisions including the ventro-dorsal stream and a third visuomotor pathway, involved in body schema and social cognition. Rehabilitation of these disorders with behavioral therapies has aimed to either restore perceptuo-semantic deficits or compensate to overcome these deficits. Further studies are required to better stratify patients, using modern neurophysiology and neuroimaging techniques, to provide targeted and personalized therapies for these disorders in the future.

Neural Correlates of Hand-Object Congruency Effects during Action Planning.

Selecting hand actions to manipulate an object is affected both by perceptual factors and by action goals. Affordances may contribute to "stimulus-response" congruency effects driven by habitual actions to an object. In previous studies, we have demonstrated an influence of the congruency between hand and object orientations on response times when reaching to turn an object, such as a cup. In this study, we investigated how the representation of hand postures triggered by planning to turn a cup was influenced by this congruency effect, in an fMRI scanning environment. Healthy participants were asked to reach and turn a real cup that was placed in front of them either in an upright orientation or upside-down. They were instructed to use a hand orientation that was either congruent or incongruent with the cup orientation. As expected, the motor responses were faster when the hand and cup orientations were congruent. There was increased activity in a network of brain regions involving object-directed actions during action planning, which included bilateral primary and extrastriate visual, medial, and superior temporal areas, as well as superior parietal, primary motor, and premotor areas in the left hemisphere. Specific activation of the dorsal premotor cortex was associated with hand-object orientation congruency during planning and prior to any action taking place. Activity in that area and its connectivity with the lateral occipito-temporal cortex increased when planning incongruent (goal-directed) actions. The increased activity in premotor areas in trials where the orientation of the hand was incongruent to that of the object suggests a role in eliciting competing representations specified by hand postures in lateral occipito-temporal cortex.

Theta burst stimulation in humans: a need for better understanding effects of brain stimulation in health and disease.

Repetitive transcranial stimulation (rTMS) paradigms have been used to induce lasting changes in brain activity and excitability. Previous methods of stimulation were long, often ineffective and produced short-lived and variable results. A new non-invasive brain stimulation technique was developed in John Rothwell's laboratory in the early 2000s, which was named 'theta burst stimulation' (TBS). This used rTMS applied in burst patterns of newly acquired 50 Hz rTMS machines, which emulated long-term potentiation/depression-like effects in brain slices. This stimulation paradigm created long-lasting changes in brain excitability, using efficient, very rapid stimulation, which would affect behaviour, with the aim to influence neurological diseases in humans. We describe the development of this technique, including findings and limitations identified since then. We discuss how pitfalls facing TBS reflect those involving both older and newer, non-invasive stimulation techniques, with suggestions of how to overcome these, using personalised, 'closed loop' stimulation methods. The challenge in most non-invasive stimulation techniques remains in identifying their exact mechanisms of action in the context of neurological disease models. The development of TBS provides the backdrop for describing John's contribution to the field, inspiring our own scientific endeavour thanks to his unconditional support, and unfailing kindness.

Factors influencing planning of a familiar grasp to an object: what it is to pick a cup.

We assessed the factors influencing the planning of actions required to manipulate one of two everyday objects with matching dimensions but openings at opposite ends: a cup and a vase. We found that, for cups, measures of movement preparation to reach and grasp the object were influenced by whether the grasp was made to the functional part of the object (wide opening) and whether the action would end in a supinated as opposed to a pronated grasp. These factors interacted such that effects of hand posture were found only when a less familiar grasp was made to the non-functional part of the cup (the base). These effects were not found with the vase, which has a less familiar location for grasping. We interpret the results in terms of a parallel model of action selection, modulated by both the familiarity of the grasp to a part of the object, likely to reflect object 'affordances' and the end state comfort of the action.

Deficits in Limb Praxis in Patients With Obsessive-Compulsive Disorder.

There is recent evidence of deficits in praxis in patients with primary dystonia. Obsessive-compulsive disorder (OCD) has been linked to disorders of higher-order motor function, such as dystonia. However, no clear mechanism underlying such a relationship has been found. This pilot study aimed to identify whether patients with OCD might also show deficits in praxis. Patients with OCD were compared with healthy volunteers on a meaningless gesture imitation task. Patients showed significantly lower scores in this task. Further studies are needed to elucidate the nature of patients' deficits in praxis. This might reveal similar mechanisms underlying OCD and some types of movement disorders.

Parietal control of hand movement.

The parietal lobe has been implicated in the sensorimotor control and integration that supports the skillful use of our hands to reach for, grasp, and manipulate objects in the environment. This area is involved in several circuits within the classic subdivisions of the dorsal stream. Recently, the dorsal stream has been further divided into a "dorso-dorsal" and a "ventro-dorsal" streams. The ventro-dorsal stream is regarded as functionally linked to object manipulation. The dorso-dorsal stream is proposed to subserve reaching and online control of actions. Affordances indicate action possibilities characterized by object properties the environment provides. Affordances are likely represented by the dorsal stream. They code structural object properties that can elicit actions. A further subdivision of affordances into "stable" and "variable" allows an understanding of the neuronal mechanisms underlying object manipulation. Whereas stable affordances emerge from slow processing of visual information based on knowledge of object properties from previous experiences and object interaction, variable affordances emerge from fast online processing of visual information during actual object interaction, within a changing environment. The relevance of the dorsal stream subdivisions in this context is that the dorso-dorsal stream is associated with coding of variable affordances, while that of the dorso-ventral stream is implicated in action representations elicited by stable affordances. A greater interaction between these and ventral stream perceptual and semantic representations allows the parietal control of hand movement. An understanding of these networks is likely to underlie recovery from complex deficits described in limb apraxias.

Characterising factors underlying praxis deficits in chronic left hemisphere stroke patients.

Limb apraxia, a disorder of skilled action not consequent on primary motor or sensory deficits, has traditionally been defined according to errors patients make on neuropsychological tasks. Previous models of the disorder have failed to provide a unified account of patients' deficits, due to heterogeneity in the patients and tasks used. In this study we hypothesised that we may be able to map apraxic deficits onto principal components, some of which may be specific, whilst others may align with other cognitive disorders. We implemented principal component analysis (PCA) to elucidate core factors of the disorder in a preliminary cohort of 41 unselected left hemisphere chronic stroke patients who were tested on a comprehensive and validated apraxia screen. Three principal components were identified: posture selection, semantic control and multi-demand sequencing. These were submitted to a lesion symptom mapping (VBCM) analysis in a subset of 24 patients, controlled for lesion volume, age and time post-stroke. The first component revealed no significant structural correlates. The second component was related to regions in inferior frontal gyrus, primary motor area, and adjacent parietal opercular (including inferior parietal and supramarginal gyrus) areas. The third component was associated with lesions within the white matter underlying the left sensorimotor cortex, likely involving the 2nd branch of the left superior longitudinal fasciculus as well as the posterior orbitofrontal cortex (pOFC). These results highlight a significant role of common cognitive functions in apraxia, which include action selection, and sequencing, whilst more specific deficits may relate to semantic control. Moreover, they suggest that previously described 'ideomotor' and 'ideational' deficits may have a common neural basis within semantic control. Further research using this technique would help elucidate the cognitive processes underlying limb apraxia, its neural correlates and their relationship with other cognitive disorders.

Antiplatelet therapy for transient ischaemic attack and minor ischaemic stroke.

Transient ischaemic attacks carry an increased risk of large ischaemic stroke in the 90 days after an event. Patients need to be seen within 24 hours in a dedicated clinic to start secondary prevention. This editorial reviews evidence for consideration of early dual antiplatelet therapy after a transient ischaemic attack.

Theta burst stimulation of the human motor cortex.

It has been 30 years since the discovery that repeated electrical stimulation of neural pathways can lead to long-term potentiation in hippocampal slices. With its relevance to processes such as learning and memory, the technique has produced a vast literature on mechanisms of synaptic plasticity in animal models. To date, the most promising method for transferring these methods to humans is repetitive transcranial magnetic stimulation (rTMS), a noninvasive method of stimulating neural pathways in the brain of conscious subjects through the intact scalp. However, effects on synaptic plasticity reported are often weak, highly variable between individuals, and rarely last longer than 30 min. Here we describe a very rapid method of conditioning the human motor cortex using rTMS that produces a controllable, consistent, long-lasting, and powerful effect on motor cortex physiology and behavior after an application period of only 20-190 s.

Factors Influencing Manipulation of a Familiar Object in Patients With Limb Apraxia After Stroke.

Previous studies have shown that hand actions to visual objects are affected both by perceptual factors and by action goals. Our aim was to study how these processes affected hand actions in chronic stroke patients, based on whether they had limb apraxia. Twenty-two left hemisphere, chronic stroke patients were measured on neuropsychological tasks of limb apraxia, which was identified in a subgroup of 10 patients. All patients underwent testing on a separate task of making simple reach and grasp actions to a cup. Their performance was compared to a group of 18 healthy age-matched volunteers. Participants were instructed to grasp the top or bottom of a cup to either lift or turn it over so as to end with a hand position that was either comfortable or uncomfortable. This task tested the influence of the compatibility of hand-cup orientation, as well as goals driven by the end-state comfort of the hand, on action selection for object manipulation. Participants' performance was measured in terms of error rates, and speed of initiation and reaching (movement time) to the object. The patients' performance was significantly delayed, and error rates increased when reaching to grasp a cup under conditions of poor compatibility and end-state comfort. The subgroup of patients with apraxia showed a decreased influence of compatibility of hand interaction with the cup, with increased error rates and delayed response times, compared to patients with no apraxia and healthy volunteers. This is despite the fact they did not display significant deficits on neuropsychological tasks of real object use. The study shows that patients with apraxia have difficulties in selecting elements of object-directed actions, pertaining to both habitual and goal-directed factors.

A Role for the Action Observation Network in Apraxia After Stroke.

Limb apraxia is a syndrome often observed after stroke that affects the ability to perform skilled actions despite intact elementary motor and sensory systems. In a large cohort of unselected stroke patients with lesions to the left, right, and bilateral hemispheres, we used voxel-based lesion-symptom mapping (VLSM) on clinical CT head images to identify the neuroanatomical correlates of the impairment of performance in three tasks investigating praxis skills in patient populations. These included a meaningless gesture imitation task, a gesture production task involving pantomiming transitive and intransitive gestures, and a gesture recognition task involving recognition of these same categories of gestures. Neocortical lesions associated with poor performance in these tasks were all in the left hemisphere. They involved the pre-striate and medial temporal cortices, the superior temporal sulcus, inferior parietal area PGi, the superior longitudinal fasciculus underlying the primary motor cortex, and the uncinate fasciculus, subserving connections between temporal and frontal regions. No significant lesions were identified when language deficits, as indicated via a picture naming task, were controlled for. The implication of the superior temporal sulcus and the anatomically connected prestriate and inferior parietal regions challenges traditional models of the disorder. The network identified has been implicated in studies of action observation, which might share cognitive functions sub-serving praxis and language skills.

Altered dorsal premotor-motor interhemispheric pathway activity in focal arm dystonia.

Given the possible role of dorsal premotor cortex (PMd) in the pathophysiology of dystonia, we used transcranial magnetic stimulation (TMS) methods to study PMd and PMd-primary motor cortex (M1) interactions in patients with focal arm dystonia. Here, we tested the connectivity between left PMd and right M1 as well as the intracortical excitability of PMd in 11 right-handed patients with focal arm/hand dystonia and nine age-matched healthy controls. The results showed that excitability of the inhibitory connection between PMd and M1 was reduced in patients, but there was no significant difference to healthy subjects in the excitability of the facilitatory connection. A triple stimulation technique in which pairs of TMS pulses are given over PMd and their interaction measured in terms of the effect on the baseline PMd-M1 connection failed to reveal the usual pattern of interaction between the pairs of PMd stimuli. Indeed, the results in patients were similar to those seen in a group of young healthy subjects after the excitability of PMd had been changed by pretreatment with high-frequency rTMS. We suggest that reduced transcallosal inhibition from the PMd may be involved in the altered pattern of abnormal muscle contractions of agonists and antagonists (overflow).

Acute changes in frontoparietal activity after repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex in a cued reaction time task.

Lesion and functional imaging studies in humans have suggested that the dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and intraparietal sulcus (IPS) are involved in orienting attention. A functional magnetic resonance imaging study supplemented by a behavioral experiment examined the effects of 5 Hz repetitive transcranial magnetic stimulation (rTMS) conditioning to the right and left DLPFC on reaction times and synaptic activity as indexed by changes in the blood oxygenation level-dependent (BOLD) signal during a cued choice reaction time task. Orienting precues were either correct (valid) or incorrect (invalid) with respect to the subsequent move cue. The effects of real and sham rTMS were compared for each site of stimulation. Invalid trials showed a significant increase in response times and increases in the BOLD signal in right frontal and parietal regions when compared with valid trials. Conditioning left DLPFC with rTMS led to decreased BOLD signal during performance of this reorienting task in areas including left VLPFC and left IPS. Comparing invalid to valid trials after right DLPFC conditioning revealed decreased BOLD signal in right VLPFC. Data from the behavioral study showed that right DLPFC rTMS selectively increases response times in invalid trials. This effect was only present in the first 10 min after rTMS conditioning. No effect was found in either validly or invalidly cued trials with left DLPFC conditioning. These results suggest that 5 Hz rTMS over right DLPFC exerts remote effects on the activity of areas that functionally interact with the DLPFC during attentional processes, particularly when the reorienting of attention is more demanding as in invalid trials.

Wallerian degeneration of the corticofugal tracts in chronic stroke: a pilot study relating diffusion tensor imaging, transcranial magnetic stimulation, and hand function.

OBJECTIVE: This study tested the hypothesis that degeneration of the corticofugal tracts (CFTs) is related to poor functional outcome in the upper limb after stroke. METHODS: . The authors used diffusion tensor imaging to determine the degree of white matter integrity of the CFT (FA(AH/UH)) in chronic stroke patients and controls. The functional integrity of the corticospinal pathway was examined using transcranial magnetic stimulation. Recruitment curves and silent period duration were measured. The relationship between FA(AH/UH) and functional outcome of the upper limb was also assessed using a battery of upper limb function tests. RESULTS: In patients, FA( AH/UH) correlated positively with the slope of recruitment curves (RC(AH/UH)) and grip strength. FA(AH/UH) also correlated negatively with the silent period duration (SP(AH/UH)). According to the FA(AH/UH), patients were also classified into groups with minimal or extensive Wallerian degeneration (WD). Patients with more extensive WD had poorer grip strength, dexterity, and range of movement. CONCLUSIONS: The authors' results suggest that structural and functional integrity of the CFT is essential to maintain function of the upper limb after stroke.

Limb apraxia and the "affordance competition hypothesis".

Limb apraxia, a disorder of higher order motor control, has long been a challenge for clinical assessment and understanding (Leiguarda and Marsden, 2000). The deficits originally described in limb apraxia (Liepmann, 1920) have been classified by the nature of the errors made by the patients leading to, namely, ideational and ideomotor apraxia. The dual stream hypothesis (Goodale and Milner, 1992) has been used to explain these categories: ideational apraxia is thought to relate to a deficit in the concept of a movement (coded in the ventral stream). Patients have difficulty using objects, sequencing actions to interact with them or pantomiming their use. Ideomotor apraxia, on the other hand, is thought to arise from problems in the accurate implementation of movements within the dorsal stream. One of the limitations on understanding apraxia is the failure by the clinical literature to draw on knowledge of the factors determining actions in the environment. Here we emphasize the role of affordance. There is much recent work indicating that our responses to stimuli are strongly influenced by the actions that the objects "afford", based on their physical properties and the intentions of the actor (e.g., Tucker and Ellis, 1998). The concept of affordance, originally suggested by Gibson (1979) has been incorporated in a recent model of interactive behavior that draws from findings in non-human primates, namely the "affordance competition hypothesis" (Cisek, 2007). This postulates that interactive behavior arises by a process of competition between possible actions elicited by the environment. In this paper we argue that "affordance competition" may play a role in apraxia. We review evidence that at least some aspects of apraxia may reflect an abnormal sensitivity to competition when multiple affordances are present (Riddoch et al., 1998) and/or a poor ability to exert cognitive control over this competition when it occurs. This framework suggests a new way of conceptualizing deficits in apraxia which invites further investigations in the field.

Theta-burst transcranial magnetic stimulation to the prefrontal cortex impairs metacognitive visual awareness.

We used a recently developed protocol of transcranial magnetic stimulation (TMS), theta-burst stimulation, to bilaterally depress activity in the dorsolateral prefrontal cortex as subjects performed a visual discrimination task. We found that TMS impaired subjects' ability to discriminate between correct and incorrect stimulus judgments. Specifically, after TMS subjects reported lower visibility levels for correctly identified stimuli, as if they were less fully aware of the quality of their visual information processing. A signal detection theory analysis confirmed that the results reflect a change in metacognitive sensitivity, not just response bias. The effect was specific to metacognition; TMS did not change stimulus discrimination performance, ruling out alternative explanations such as TMS impairing visual attention. Together these results suggest that activations in the prefrontal cortex in brain imaging experiments on visual awareness are not epiphenomena, but rather may reflect a critical metacognitive process.

Effects of rTMS conditioning over the fronto-parietal network on motor versus visual attention.

Many studies have shown that visuospatial orienting attention depends on a network of frontal and parietal areas in the right hemisphere. Rushworth et al. [Rushworth, M. F., Krams, M., & Passingham, R. E. The attentional role of the left parietal cortex: The distinct lateralization and localization of motor attention in the human brain. Journal of Cognitive Neuroscience, 13, 698-710, 2001] have recently provided evidence for a left-lateralized network of parietal areas involved in motor attention. Using two variants of a cued reaction time (RT) task, we set out to investigate whether high-frequency repetitive transcranial magnetic stimulation (rTMS; 5 Hz) delivered "off-line" in a virtual lesion paradigm over the right or left dorsolateral prefrontal cortex (DLPFC) or the posterior parietal cortex (PPC) would affect performance in a motor versus a visual attention task. Although rTMS over the DLPFC on either side did not affect RT performance on a spatial orienting task, it did lead to an increase in the RTs of invalidly cued trials in a motor attention task when delivered to the left DLPFC. The opposite effect was found when rTMS was delivered to the PPC: In this case, conditioning the right PPC led to increased RTs in invalidly cued trials located in the left hemispace, in the spatial orienting task. rTMS over the PPC on either side did not affect performance in the motor attention task. This double dissociation was evident in the first 10 min after rTMS conditioning. These results enhance our understanding of the networks associated with attention. They provide evidence of a role for the left DLPFC in the mechanisms of motor preparation, and confirm Mesulam's original proposal for a right PPC dominance in spatial attention [Mesulam, M. M. A cortical network for directed attention and unilateral neglect. Annals of Neurology, 10, 309-325, 1981].

Frequency specific changes in regional cerebral blood flow and motor system connectivity following rTMS to the primary motor cortex.

Repetitive transcranial magnetic stimulation (rTMS) to the human primary motor cortex (M1) causes bidirectional changes in corticospinal excitability depending on the stimulation frequency used. We used functional brain imaging to compare the effects of 5 Hz and 1 Hz-rTMS on local and inter-regional connectivity within the motor system. Regional cerebral blood flow (rCBF) was measured as a marker of synaptic activity at rest and during freely selected finger movements. We hypothesized that increased cortical excitability induced by 5 Hz-rTMS over M1 has an opposite effect on the synaptic activity and the connectivity of the motor network from the decreased cortical excitability induced by 1 Hz-rTMS. rTMS at both frequencies induced similar changes in rCBF at the site of stimulation and within areas of the motor network engaged by the task. The two frequencies showed different effects on movement-related coupling between motor areas. Connectivity analyses also indicated a differential effect of 5 and 1 Hz-rTMS on motor network connectivity, suggesting a role for an inferomedial portion of left M1 and left dorsal premotor cortex in maintaining performance. These results suggest that rapid reorganization of the motor system occurs to maintain task performance during periods of altered cortical excitability. This reorganization differs according to the modulation of excitability which is a function of rTMS frequency. This study extends the work of Lee et al. (Lee, L., Siebner, H.R., Rowe, J.B., Rizzo, V. Rothwell, J.C. Frackowiak, R.S. Friston, K.J., 2003. Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J. Neurosci. 23, 5308-5318.) by providing evidence that the pattern of acute reorganization in the motor network following rTMS depends on the direction of conditioning.