[Networks involved in motor cognition : Physiology and pathophysiology of apraxia]. / Netzwerke für motorische Kognition : Physiologie und Pathophysiologie der Apraxie.

Apraxia is an umbrella term for different disorders of higher motor abilities that are not explained by elementary sensorimotor deficits (e. g. paresis or ataxia). Characteristic features of apraxia that are easy to recognize in clinical practice are difficulties in pantomimed or actual use of tools as well as in imitation of meaningless gestures. Apraxia is bilateral, explaining the cognitive motor disorders and occurs frequently (but not exclusively) after left hemispheric lesions, as well as in neurodegenerative diseases, such as corticobasal syndrome and Alzheimer's disease. Apraxic deficits can seriously impair activities of daily living, which is why the appropriate diagnosis is of great relevance. At the functional anatomical level, different cognitive motor skills rely on at least partly different brain networks, namely, a ventral processing pathway for semantic components, such as tool-action associations, a ventro-dorsal pathway for sensorimotor representations of learnt motor acts, as well as a dorso-dorsal pathway for on-line motor control and, probably, imitation of meaningless gestures. While these networks partially overlap with language-relevant regions, more clear cut dissociations are found between apraxia deficits and disorders of spatial attention. In addition to behavioral interventions, noninvasive neuromodulation approaches, as well as human-computer interface assistance systems are a growing focus of interest for the treatment of apraxia.

[A New Diagnostic Tool for Apraxia in Patients with Right-Hemisphere Stroke: The Revised Cologne Apraxia Screening (KAS-R)]. / Das revidierte Kölner Apraxie-Screening (KAS-R) als diagnostisches Verfahren für Patienten mit rechtshemisphärischem Schlaganfall.

The Cologne Apraxia Screening (KAS) was developed to diagnose apraxia following left-hemisphere (LH) stroke. The present study aims at developing a diagnostic tool for patients with right-hemisphere (RH) stroke (KAS-R) by modifying the test material of the KAS and reducing the test items based on psychometric analyses.A total of 100 patients with RH stroke and 77 healthy control participants were tested. Psychometric analyses led to the exclusion of 8 KAS items. The final KAS-R, consisting of 12 items, shows good internal consistency (α = 0.795) as well as high sensitivity (79.4 %) and specificity (84.4 %). Applying a cut-off value of ≤ 46 (out of 48) points, 39 RH stroke patients were diagnosed with apraxia. Significant correlations were found between the KAS-R and an imitation test as well as expert ratings, indicating high construct validity. The results suggest that the KAS-R is a reliable and valid diagnostic tool for apraxic deficits after RH stroke.

Pharmacological treatment of deep brain stimulation-induced hypomania leads to clinical remission while preserving motor benefits.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease, but can lead to adverse effects including psychiatric disturbance. Little is known about the risk factors and treatment options for such effects. Here, we describe a patient who reproducibly developed stimulation-induced hypomania when using ventrally located electrodes and responded well to pharmacological intervention while leaving the stimulation parameters unchanged to preserve motor benefits. In spite of clinical remission, [¹5O]-positron-emission-tomography (PET) demonstrated activation patterns similar to those reported during mania. This case, therefore, highlights an important treatment option of adverse effects of DBS, but also points toward the need for investigations of its risk factors and their underlying neurobiological mechanisms.

The impact of apraxia and neglect on early rehabilitation outcome after stroke.

BACKGROUND: This study aims to characterize the impact of apraxia and visuospatial neglect on stroke patients' cognitive and functional outcomes during early rehabilitation. Prior work implies an unfavorable effect of visuospatial neglect on rehabilitation; however, previous findings remain ambiguous and primarily considered long-term effects. Even less is known about the impact of apraxia on rehabilitation outcomes. Although clinicians agree on the significance of the first few weeks after stroke for the course of rehabilitation, studies exploring the impact of neglect and apraxia in this early rehabilitation period remain scarce. METHODS: Based on a screening of 515 hospitalized stroke patients from an early rehabilitation ward, 150 stroke patients (75 left-hemispheric strokes, 75 right hemispheric strokes) fulfilled the inclusion criteria and were enrolled in this observational, longitudinal study. The patients' cognitive and functional statuses were documented at admission to the early rehabilitation ward and discharge. Also, detailed apraxia and neglect assessments were performed at midterm. The predictive values of age and apraxia and neglect severity (as reflected in two components from a principal component analysis of the neglect and apraxia assessments) for cognitive and functional outcomes at discharge were evaluated by multiple regression analyses. RESULTS: Besides the expected influence of the respective variables at admission, we observed a significant effect of apraxia severity on the cognitive outcome at discharge. Moreover, neglect severity predicted the Early Rehabilitation Barthel Index (Frühreha-Barthel-Index) at discharge. Supplementary moderator analysis revealed a differential effect of neglect severity on the cognitive outcome depending on the affected hemisphere. CONCLUSION: Data indicate a strong association between apraxia and visuospatial neglect and early rehabilitation outcomes after stroke.

Visual extinction in relation to visuospatial neglect after right-hemispheric stroke: quantitative assessment and statistical lesion-symptom mapping.

BACKGROUND: Visual neglect and extinction are two common neurological syndromes in patients with right-hemispheric brain damage. Whether and how these two syndromes are associated or share common neural substrates is still a matter of debate. METHODS: To address these issues, the authors investigated 56 patients with right-hemispheric stroke with a novel diagnostic test to detect extinction and neglect. In this computerised task, subjects had to respond to target stimuli in uni- and bilateral stimulation conditions with detection probabilities being assessed. A cluster-analytical approach identified 18 patients with neglect and 13 patients with extinction. Statistical lesion-symptom mapping analyses with measures for extinction and neglect were performed. RESULTS: Extinction and neglect co-occurred in a subset of patients but were also observed independently from each other, thereby constituting a double dissociation. Lesions within the right inferior parietal cortex were significantly associated with the severity of visual extinction. Visuospatial neglect was related to damage of fronto-parietal brain regions, with parieto-occipital areas affecting line bisection and dorsal fronto-parietal areas affecting cancellation task performance, respectively. CONCLUSION: Quantifying lesion-induced symptoms with this novel paradigm shows that extinction and neglect are dissociable syndromes in patients with right-hemispheric stroke. Furthermore, extinction and neglect can be related to differential neural substrates, with extinction being related to focal brain damage within the right inferior parietal cortex.

[How to diagnose and treat limb apraxia]. / Diagnostik und Therapie der Gliedmabenapraxie.

Apraxia is a disorder of higher motor cognition. Deficits in imitating abstract and symbolic gestures as well as deficits in appropriate tool use are common apraxic symptoms which, importantly, cannot be explained by primary sensorimotor deficits alone. In spite of the relevance of apraxia for neurorehabilitation and the individual stroke patient's prognosis, apraxia is to date still too rarely diagnosed and treated. In this review the currently published assessments for the diagnosis of apraxia are evaluated. Based on this, an apraxia screening instrument as well as a diagnostic test for clinical use are recommended. In addition, different published approaches to the therapy for apraxia are described. Although current evidence is scarce, the gesture training suggested by Smania and co-workers can be recommended as a therapy for apraxia, because its effects were shown to extend to activities of daily living and to persist for at least two months after completion of the training. This review aims at directing the clinician's attention to the importance of apraxia. Moreover, it provides the interested reader with instruments for a reliable diagnosis and effective treatment of apraxia. These are also important prerequisites for further research into the neurobiological mechanisms underlying apraxia and the development of new therapy strategies leading to an evidence-based effective treatment of apraxia.

[Structural and functional neuroimaging of the pathophysiology of apraxia]. / Strukturelle und funktionelle Bildgebung zur Pathophysiologie der Apraxie.

A better understanding of the neural bases of apraxia is an important prerequisite to develop new therapeutic strategies for the disabling apraxic deficits after left-hemisphere stroke, like disturbed imitation of gestures, deficient pantomime, and object use deficits. Recently, functional and structural imaging methods allowed deeper insights into the pathophysiology of apraxia: While apraxic object use deficits result from the dysfunction of an extended fronto-parietal network within the left hemisphere, pantomime deficits are caused by impaired functioning of the left inferior frontal cortex. Further apraxia-related, motor cognitive processes (i.e., gesture imitation, integration of temporal and spatial movement information, and intentional movement planning) depend on the integrity of the left parietal cortex. Newly developed functional and structural imaging methods, like dynamic causal modelling (DCM) and diffusion tensor imaging (DTI), promise to further elucidate the pathophysiology of apraxia at the network level.

Recovery from apraxic deficits and its neural correlate.

BACKGROUND AND OBJECTIVE: Apraxia is a deficit of motor cognition leading to difficulties in actual tool use, imitation of gestures, and pantomiming object use. To date, little data exist regarding the recovery from apraxic deficits after stroke, and no statistical lesion mapping study investigated the neural correlate of recovery from apraxia. Accordingly, we here examined recovery from apraxic deficits, differential associations of apraxia task (imitation vs. pantomime) and effector (bucco-facial vs. limb apraxia) with recovery, and the underlying neural correlates. METHODS: We assessed apraxia in 39 patients with left hemisphere (LH) stroke both at admission and approximately 11 days later. Furthermore, we collected clinical imaging data to identify brain regions associated with recovery from apraxic deficits using voxel-based lesion-symptom mapping (VLSM). RESULTS: Between the two assessments, a significant recovery from apraxic deficits was observed with a tendency of enhanced recovery of limb compared to bucco-facial apraxia. VLSM analyses revealed that within the lesion pattern initially associated with apraxia, lesions of the left insula were associated with remission of apraxic deficits, whereas lesions to the (inferior) parietal lobe (IPL; supramarginal and angular gyrus) and the superior longitudinal fasciculus (SLF) were associated with persistent apraxic deficits. CONCLUSIONS: Data suggest that lesions affecting the core regions (and white matter) of the fronto-parietal praxis network cause more persistent apraxic deficits than lesions affecting other regions (here: the left insula) that also contribute to motor cognition and apraxic deficits.

The quantitative relationship of urinary peptide hydroxyproline excretion to collagen degradation.

To determine the quantitative relationship of urinary hydroxyproline peptide excretion to collagen breakdown, known quantities of radioactive hydroxyproline peptides were administered to unlabeled animals and excertion of radioactivity in respiratory carbon dioxide, urine, and feces was measured. The major routes of excretion of collagen peptide metabolites were respiratory carbon dioxide (75%) and urine, as hydroxyproline-containing peptides (25%). Since the predominant urine hydroxyproline peptide linkage is proly-hydroxyproline, L-prolyl-L-hydroxyproline-(3)H was administered to unlabeled animals. Greater than 80% of the administered dipeptide was excreted in urine, suggesting that this peptide linkage is not hydrolyzed to a significant extent in vivo. These data suggest that urinary hydroxyproline excretion is a "fairly" sensitive indicator of collagen breakdown and can be used at the clinical level to quantitate changes in collagen breakdown.

Dipyridamole/aspirin combination in secondary stroke prevention: effects on absolute myocardial blood flow and coronary vascular resistance.

OBJECTIVE: In the European Stroke Prevention Study (ESPS 2), oral administration of a fixed combination of 200 mg extended-release dipyridamole and 25 mg aspirin (twice daily) after ischemic stroke or transient ischemic attack, significantly reduced the risk of stroke compared to placebo as well as compared to aspirin or dipyridamole alone. However, the i.v. application of dipyridamole over 4 - 6 min is known to increase myocardial blood flow up to 6-fold, and thereby potentially provoke ischemic wall motion abnormalities in patients with coronary artery disease. We therefore assessed the cardiac side effects of the dipyridamole/aspirin combination on absolute myocardial blood flow (MBF) and coronary vascular resistance (CVR). METHODS: MBF and CVR were measured using 150-water positron emission tomography in 24 patients after stroke or transient ischemic attack, before and 6.7 +/- 1.9 days after starting the dipyridamole/aspirin combination (Aggrenox) therapy. RESULTS: Resting MBF increased by 39% (max. 112%), from 0.92 +/- 0.13 (ml x g(-1) x min(-1)) at baseline to 1.28 +/- 0.27 (ml x g(-1) x min(-1)) under ongoing dipyridamole/aspirin combination therapy (p < 0.0005). CVR consecutively decreased from 105.3 +/- 16.9 to 74.1 +/- 16.5 (mmHg x ml(-1) x g x min) (p < 0.0005). The relative increase in MBF correlated negatively with the body surface area. No correlation was found between relative MBF increase and duration of dipyridamole/aspirin combination therapy (range 4 - 10 days). CONCLUSIONS: Orally administered dipyridamole/aspirin combination therapy in secondary stroke prevention increases MBF and decreases CVR significantly. These cardiac side effects of the dipyridamole/aspirin combination should be taken into account in stroke patients with proven or suspected coronary artery disease, particularly in combination with a small body surface area.

Effect of meaning on apraxic finger imitation deficits.

Apraxia typically results from left-hemispheric (LH), but also from right-hemispheric (RH) stroke, and often impairs gesture imitation. Especially in LH stroke, it is important to differentiate apraxia-induced gesture imitation deficits from those due to co-morbid aphasia and associated semantic deficits, possibly influencing the imitation of meaningful (MF) gestures. To explore this issue, we first investigated if the 10 supposedly meaningless (ML) gestures of a widely used finger imitation test really carry no meaning, or if the test also contains MF gestures, by asking healthy subjects (n=45) to classify these gestures as MF or ML. Most healthy subjects (98%) classified three of the 10 gestures as clearly MF. Only two gestures were considered predominantly ML. We next assessed how imitation in stroke patients (255 LH, 113 RH stroke) is influenced by gesture meaning and how aphasia influences imitation of LH stroke patients (n=208). All patients and especially patients with imitation deficits (17% of LH, 27% of RH stroke patients) imitated MF gestures significantly better than ML gestures. Importantly, meaningfulness-scores of all 10 gestures significantly predicted imitation scores of patients with imitation deficits. Furthermore, especially in LH stroke patients with imitation deficits, the severity of aphasia significantly influenced the imitation of MF, but not ML gestures. Our findings in a large patient cohort support current cognitive models of imitation and strongly suggest that ML gestures are particularly sensitive to detect imitation deficits while minimising confounding effects of aphasia which affect the imitation of MF gestures in LH stroke patients.

Safety and efficacy of pallidal or subthalamic nucleus stimulation in advanced PD.

The authors retrospectively compared 1-year results of bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN; n = 16) and internal pallidum (GPi) (n = 11) in advanced PD and found about equal improvements in "off" period motor symptoms, dyskinesias, and fluctuations. STN stimulation reduced medication requirements by 65% and required significantly less electrical power. These advantages contrasted with a need for more intensive postoperative monitoring and a higher incidence of adverse events related to levodopa withdrawal.

Line bisection judgments implicate right parietal cortex and cerebellum as assessed by fMRI.

OBJECTIVE: To use functional MRI (fMRI) to determine which brain regions are implicated when normal volunteers judge whether pretransected horizontal lines are correctly bisected (the Landmark test). BACKGROUND: Manual line bisection and a variant thereof involving perceptual judgments of pretransected lines (the Landmark test) are widely used to assess unilateral visuospatial neglect in patients with neurologic disease. Although unilateral (left) neglect most often results from lesions to right temporoparietal cortex, the normal functional anatomy of the Landmark test has not been convincingly demonstrated. METHODS: fMRI was carried out in 12 healthy right-handed male volunteers who judged whether horizontal lines were correctly prebisected. In the control task, subjects detected whether the horizontal lines contained a transection mark irrespective of the position of that mark. Response was by two-choice key press: on half the trials, subjects used the right, and on half, the left hand. Statistical analysis of evoked blood oxygenation level-dependent responses, measured with echoplanar imaging, employed statistical parametric mapping. RESULTS: Performing the Landmark task showed neural activity (p < 0.05, corrected) in the right superior posterior and right inferior parietal lobe, early visual processing areas bilaterally, the cerebellar vermis, and the left cerebellar hemisphere. Only the latter area showed a significant interaction with hand used. CONCLUSIONS: The right hemispheric dominance observed in inferior parietal cortex is consistent with the results of lesion studies. Right superior parietal cortex, vermis, and left cerebellar hemisphere have not been implicated in neglect, but all appear to play a cognitive role in the Landmark task.

Is the organisation of goal-directed action modality specific? A common temporal structure.

With the help of kinematic analysis, the temporal organization of the complex daily activity 'drinking from a bottle with a glass' was described in detail. The analysis focused on the sequential action structure, the prehensile acts, and the bimanual coordination as well as on the effect of different instruction modalities on these parameters to explore the underlying representation for this complex action. Movements of the two arms were recorded in three-dimensional space with the help of an optoelectronic device in 12 normal subjects under four conditions: (1) action pantomime after verbal instruction; (2) action imitation after observation of the action performed by the experimenter without the objects; (3) action pantomime while seeing, but not touching the objects; and finally (4) action execution with objects. Despite high execution variability, the temporal structure of the action could be precisely described by the relative duration and peak velocity of action segments, by the MGA-object size-correlation, and by linear regression analysis between the onsets of functionally related action segments. A similar structure of the action as characterized by these kinematic parameters was retained across different instruction modalities. Only when the action was executed with the objects, the interval between the movement onsets of either hand and the peak velocity of the manipulative acts were reduced, while no change was observed across the other three instruction modalities. This stability of the temporal structure suggests the existence of a level in the representation of an action where all the modalities converge.

Task instructions influence the cognitive strategies involved in line bisection judgements: evidence from modulated neural mechanisms revealed by fMRI.

Manual line bisection and a perceptual variant thereof (the Landmark test) are widely used to assess visuospatial neglect in neurological patients, but little is known about the cognitive strategies involved. In the Landmark test, one could explicitly compare the lengths of the left and right line segments; alternatively, one could compute the centre of mass of the display. We here investigate with functional MRI if these cognitive strategies modulate the neural mechanisms underlying judgements whether pre-transected horizontal lines are correctly bisected (the Landmark test) in normal volunteers. Functional neuroimaging (fMRI) was carried out in 12 healthy volunteers who judged: (a) whether the line segments on either side of the transection mark were of equal length, and (b) whether the transection mark was in the centre of the line. Line centre judgements were made significantly faster than line length comparisons. Increased neural activity common to both strategies was observed in inferior parietal lobes bilaterally and right temporooccipital cortex. Further activations, most likely reflecting general task demands like response selection and motor control, were found in the precentral gyrus bilaterally, supplementary motor area bilaterally, right anterior cingulate, right dorsolateral prefrontal cortex, cerebellar vermis, and right thalamus and right putamen. Explicit length comparisons (relative to line centre judgements) differentially activated left superior posterior parietal cortex, with a tendency toward activation of the equivalent area on the right, while the reverse comparison revealed differential activation in the lingual gyrus bilaterally and anterior cingulate cortex. The activations observed in inferior parietal cortex during task performance using either strategy are consistent with the results of lesion studies. The differential activation of superior posterior parietal cortex following length instructions suggests that explicit comparisons of spatial extent were implicated. The differential activation of bilateral occipital cortex following centre judgements suggests that the centre of a line is extracted at an early stage of visual processing.

Motor impairment in patients with parietal lesions: disturbances of meaningless arm movement sequences.

The execution of meaningless movement sequences was studied in 12 patients with lesions of the parietal cortex in comparison to the performance of age- and sex-matched controls. Five sequences of increasing complexity had to be performed by imitation and after verbal instruction. The performance errors were qualitatively scored by means of four error categories (temporal or spatial error, addition or omission of movement components). This study examined whether the error scores depended on instruction modality, movement complexity or lesion side. Patients with left parietal lesions produced more errors than those with right parietal lesions and control subjects. While additions or omissions of movement components occurred almost equally in all groups, temporal and spatial errors were more frequent in patients with left parietal lesions only. In addition, only the latter group showed a significant increase of error rates with increasing movement complexity. There were no significant differences between the contra- and ipsilesional hand in any group. These results demonstrate that lesions in the left parietal lobe lead to a disturbed spatio-temporal organisation of movement that becomes increasingly prominent for more complex movements.

'Where' depends on 'what': a differential functional anatomy for position discrimination in one- versus two-dimensions.

Line bisection is widely used as a clinical test of spatial cognition in patients with left visuospatial neglect after right hemisphere lesion. Surprisingly, many neglect patients who show severe impairment on marking the center of horizontal lines can accurately mark the center of squares. That these patients with left neglect are also typically poor at judging whether lines are correctly prebisected implies that the deficit can be perceptual rather than motoric. These findings suggest a differential neural basis for one- and two-dimensional visual position discrimination that we investigated with functional neuroimaging (fMRI). Normal subjects judged whether, in premarked lines or squares, the mark was placed centrally. Line center judgements differentially activated right parietal cortex, while square center judgements differentially activated the lingual gyrus bilaterally. These distinct neural bases for one- and two-dimensional visuospatial judgements help explain the observed clinical dissociations by showing that as a stimulus becomes a better, more 'object-like' gestalt, the ventral visuoperceptive route assumes more responsibility for assessing position within the object.

The importance of seeing it coming: a functional magnetic resonance imaging study of motion-in-depth towards the human observer.

Despite their crucial biological relevance, the neural structures differentially activated by the detection of optic flow towards the observer remain to be elucidated. Here, we deploy functional magnetic resonance imaging with normal volunteers to locate the areas differentially activated when motion towards the observer is detected. Motion towards the observer, compared with motion away, showed significant activations (P<0.05, corrected for multiple comparisons), as assessed using statistical parametric mapping, in the lateral inferior occipital cortex bilaterally and in right lateral superior occipital cortex. The areas implicated do not extend into area V5 or subdivisions thereof.Our data suggest that the representations of motion towards the observer implicate perceptual and attentional mechanisms acting at early stages of visual processing in extrastriate cortex. From the standpoint of efficient biological engineering, it makes sense that such crucially important functions as object motion towards the observer would be computed in early visual processing areas. Further studies will be required to determine the extent to which the effects we observed in lateral occipital cortex reflect differential attention to different types of motion, as contrasted with the derivation of explicit representations of motion towards the observer.

A functional magnetic resonance imaging study of local/global processing with stimulus presentation in the peripheral visual hemifields.

When stimuli are presented in the left or right visual fields, hemispheric specialization for global and local processing in occipital areas is attenuated. Using functional magnetic resonance imaging, we investigated how this attenuation is compensated for when information must cross the corpus callosum to reach the areas specialized for global and local processing. We presented hierarchically nested letters (e.g. a large E made of smaller E's) to the right or the left visual hemifield while subjects fixated centrally. In half the trials, subjects indicated whether the global aspect and in the other half whether the local aspect of the stimulus matched a pre-specified target letter. Visual hemifield presentations showed the expected contralateral activations of occipital cortex. The main effects of locally or globally directed attention did not show any differential occipital activations, but the right anterior cingulate cortex was activated differentially during local processing. Region-of-interest-based analyses showed increased neural activity in left posterior occipital cortex during local processing when stimuli were presented in the left hemifield. During global processing with stimulus presentation to the right hemifield, the right posterior occipital cortex was activated. Activation of right anterior cingulate cortex during local processing is likely to reflect the suppression of global processing precedence in order to select correctly the local stimulus level. The activations in left (local) and right (global) occipital areas are likely to reflect the top-down augmentation of stimulus information that has been degraded by callosal crossing in order to access the hemisphere specialized for local or global processing.