Executive functions in aphasia: A novel aphasia screening for cognitive flexibility in everyday communication.

Besides language deficits, persons with aphasia can present with impairments in executive functions such as cognitive flexibility. Since these impairments can restrict communicative abilities, diagnostics for aphasia should include their assessment. However, tests of executive functions, including symptoms expressed in everyday communication, are lacking for aphasia. Thus, our aim was to fill this gap and study the basic psychometric properties of the novel Cognitive Flexibility in Aphasia Screening. For a pilot evaluation, 26 German patients were examined with tests for language and cognitive flexibility as well as the novel screening. Moreover, 20 non-aphasic persons conducted the latter. We performed a Receiver Operating Characteristic analysis to investigate specificity and sensitivity, and multidimensional scaling to examine similarities between the screening and language/cognitive skills. We found good specificity and sensitivity and showed that the screening is correlated with language skills and verbal cognitive flexibility, revealing promising construct validity and feasibility of the new screening.

Combined space and alertness related therapy of visual hemineglect: effect of therapy frequency.

The combined efficacy of space- and alertness related training in chronic hemineglect was tested behaviorally and in a longitudinal fMRI study. Earlier results had shown that both space as well as alertness related training as single intervention methods lead to short term improvement which, however, is not stable for longer time periods. The neurobiological data obtained in these studies revealed differential cortical reorganization patterns for the two training approaches thereby leading to the hypothesis that a combination of both trainings might result in stronger and longer lasting effects. The results of our current study, however, - at least at first glance - do not clearly corroborate this hypothesis, because neither alertness training alone nor the combination with OKS on the group level led to significant behavioral improvement, although four of the six patients after alertness and even more after combined training showed a higher percentage of behavioral improvement than during baseline. Despite the lack of clearcut behavioral training induced improvement we found right parietal or fronto-parietal increase of activation in the imaging data immediately after combined training and at follow-up 3 weeks later. The study design had called for splitting up training time between the two training approaches in order to match total training time with our earlier single training studies. The results of our current study are discussed as a possible consequence of reduced training time and intensity of both training measures under the combined training situation.

Differential role of the Mentalizing and the Mirror Neuron system in the imitation of communicative gestures.

Successful social interaction requires recognising the intention of another person's communicative gestures. At a neural level, this process may involve neural activity in different systems, such as the mentalizing system (MS) and the mirror neuron system (MNS). The aim of the present study was to explore the neural correlates of communicative gestures during observation and execution of these gestures. Twenty participants watched video clips of an actor executing social gestures (S), non-social gestures (NS) and meaningless gestures (ML). During fMRI data acquisition, participants were asked to observe (O) and subsequently to execute (E) one of two tasks: imitate the gesture presented (IMI) or perform a motor control task (CT). For the contrast IMI>CT we found activations in the core areas of the MNS [inferior parietal lobule (IPL) and inferior frontal cortex, the posterior part of pars opercularis], as well as in areas related to the MS [superior temporal sulcus (STS) and middle cingulate cortex]. For S>NS, we found activations in the left medial orbitofrontal cortex (mOFC), right superior frontal cortex and middle cingulate cortex. The interaction of stimulus condition (S vs NS) and task (IMI vs CT) revealed activation in the right IPL. For the interaction between observation vs execution (O vs E), task (IMI vs CT) and stimulus condition (S vs NS) we found activation in the right mOFC. Our data suggest that imitation is differentially processed in the MNS as well as in the MS. The activation in IPL is enhanced during the processing of social gestures most likely due to their communicative intention. The activation of IPL together with medial frontal areas may contribute to mentalizing processes. The interaction in the mOFC suggests an involvement of self-referential processes in the processing of social gesture.

Progression of subtle motor signs in PINK1 mutation carriers with mild dopaminergic deficit.

BACKGROUND: While homozygous mutations in the PINK1 gene cause recessively inherited early-onset Parkinson disease (PD), heterozygous mutations have been suggested as a susceptibility factor. METHODS: To evaluate this hypothesis, 4 homozygous PINK1 patients with PD and 10 asymptomatic carriers of a single heterozygous mutation from a large German family (family W) were included in this study. Clinical follow-up of the heterozygous mutation carriers 3 years after the initial visit included a detailed videotaped neurologic examination using the Unified Parkinson's Disease Rating Scale III protocol and smell and color discrimination testing. At follow-up, PET with 18-fluorodopa (FDOPA) of 13 family members was obtained in order to evaluate the clinical phenotype in light of nigostriatal dopaminergic functioning. The clinical and PET data were compared to those of healthy controls. RESULTS: While there was mild worsening of clinical signs in previously affected heterozygous mutation carriers upon follow-up, 3 additional individuals had newly developed signs of possible PD. Hyposmia was found in 7 of the heterozygous mutation carriers, diminished color discrimination in 4. The homozygous mutation carriers who were all definitely affected with PD showed a severe, 60% decrease of caudate and putaminal FDOPA uptake; heterozygous offspring also had a significant 20% putaminal FDOPA uptake reduction compared to controls. CONCLUSIONS: Our findings strengthen the hypothesis that heterozygous PINK1 mutations act as a susceptibility factor to develop at least subtle Parkinson disease motor and nonmotor signs, as supported by the finding of a reduced striatal dopaminergic FDOPA uptake not only in homozygous but also, albeit to a lesser extent, in heterozygous mutation carriers.

The role of ipsilateral primary motor cortex in movement control and recovery from brain damage.

The role of ipsilateral motor areas for movement control is not yet fully understood. The relevance of these areas to the recovery of motor function following a brain lesion is a matter of dispute. It has recently been stated that increased ipsilateral activation following brain damage is maladaptive and hindering the process of recovery. Others have presented evidence that ipsilateral motor areas subserve motor recovery. A recent study published in Experimental Neurology [Lotze, M., Sauseng, P., Staudt, M., 2009. Functional relevance of ipsilateral motor activation in congenital hemiparesis as tested by fMRI-navigated TMS. Exp. Neurol., 217, 440-443.] on patients with congenital hemiparesis presents evidence for the importance of ipsilateral primary motor cortex and dorsal premotor cortex to movement control even in the absence of direct ipsilateral descending output in this special set of patients. This comment briefly summarizes the relevant findings supporting both views and discusses potential causes for the prima facie contradictory findings.

Parietal modules for reaching.

Optic ataxia (OA) is classically defined as a deficit of visually guided movements that follows lesions of the posterior part of the posterior parietal cortex (PPC). Since the formalisation of the double stream of visual information processing [Milner, A. D., & Goodale, M. A. (1995). The visual brain in action. Oxford: Oxford University Press] and the use of OA as an argument in favour of the involvement of the posterior parietal cortex (dorsal stream) in visually guided movements, many studies have looked at the visuomotor deficits of these patients. In parallel, the development of neuroimaging methods have led to increasing information about the role of the posterior parietal cortex in visually guided actions. In this article, we discuss the similarities and differences in the results that emerged from these two complementary viewpoints by combining a meta-analysis of neuroimaging data on reaching with lesion studies from OA patients and results of our own fMRI study on reaching in the ipsi- and contra-lateral visual field. We identified four bilateral parietal foci from the meta-analysis and found that the more posterior foci showed greater lateralisation for contralateral visual stimulation than more anterior ones Additionally, the more anterior foci showed greater lateralisation for the use of the contralateral hand than the more posterior ones. Therefore, we can demonstrate that they are organised along a postero-anterior gradient of visual-to-somatic information integration. Furthermore, from the combination of imaging and lesion data it can be inferred that a lesion of the three most posterior foci responsible for the target-hand integration could explain the hand and field effect revealed in OA reaching behaviour.

Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype.

OBJECTIVE: To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements. METHODS: Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype. RESULTS: Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation. CONCLUSION: Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.

Morphometric fingerprint of asymptomatic Parkin and PINK1 mutation carriers in the basal ganglia.

BACKGROUND: Mutations in the Parkin and PINK1 genes can cause parkinsonism. Since asymptomatic carriers of a single mutant allele of the Parkin or PINK1 gene display a presynaptic dopaminergic dysfunction in the striatum, they provide a unique in vivo model to study structural and functional reorganization in response to latent nigrostriatal dysfunction. We hypothesized that subclinical nigrostriatal neurodegeneration caused by these mutations would induce morphologic changes in the dysfunctional striatal gray matter. METHODS: In asymptomatic carriers of a heterozygous Parkin (n = 13) or PINK1 (n = 10) mutation and 23 age-and sex-matched individuals without a mutation, we applied observer independent region-of-interest and voxel-based morphometry to high-resolution structural MRIs. RESULTS: Relative to controls without a mutation, Parkin and PINK1 mutation carriers displayed a bilateral increase in gray matter volume in the putamen and the internal globus pallidus. In 8 of the 13 Parkin mutation carriers, the presynaptic dopaminergic function was studied with (18)F-DOPA PET. The metabolic-morphometric regression analysis revealed that the linear decrease in individual presynaptic striatal (18)F-DOPA uptake was linked to a reciprocal decrease in the striatal gray matter volume in the putamen bilaterally and in the left caudate nucleus. CONCLUSIONS: The alternative causes of the increased striatal gray matter volume may be either due to excessive levels of neuronal activity caused by chronic dopaminergic dysfunction or due to long-term adaptation to chronic nigrostriatal dysfunction actively compensating for the dopaminergic denervation. In any case, the results indicate that a genetically driven regional dysfunction may be imprinted in the structure of the dysfunctional brain region, for example in the striatum.

Morphological basis for the spectrum of clinical deficits in spinocerebellar ataxia 17 (SCA17).

Spinocerebellar ataxia 17 (SCA17) is a rare genetic disorder characterized by cerebellar, extrapyramidal, pyramidal as well as psychiatric signs. The pathoanatomical basis of this disorder is still not well known. A total of 12 patients and 12 age- and sex-matched controls were examined by in vivo MRI voxel-based morphometry (VBM). Besides general patterns of disease-related brain atrophy, characteristic syndrome-related morphological changes in SCA17 patients were studied. In comparison with normal controls, SCA17 patients showed a pattern of degeneration of the grey matter centred around mesial cerebellar structures, occipito-parietal structures, the anterior putamen bilaterally, the thalamus and other parts of the motor network, reflecting the cerebellar, pyramidal and extrapyramidal signs. A correlation analysis revealed a clear association between the clinical cerebellar, extrapyramidal and psychiatric scores and degeneration in specific areas. Two degeneration patterns were found as follows: regarding motor dysfunction, atrophy of the grey matter involved mainly the cerebellum and other motor networks, in particular the basal ganglia. In contrast, correlations with psychiatric scores revealed grey matter degeneration patterns in the frontal and temporal lobe, the cuneus and cingulum. Most interestingly, there was a highly significant correlation between the clinical Mini-Mental State Examination scores and atrophy of the nucleus accumbens, probably accounting for the leading psychiatric signs.

No double-dissociation between optic ataxia and visual agnosia: multiple sub-streams for multiple visuo-manual integrations.

The current dominant view of the visual system is marked by the functional and anatomical dissociation between a ventral stream specialised for perception and a dorsal stream specialised for action. The "double-dissociation" between visual agnosia (VA), a deficit of visual recognition, and optic ataxia (OA), a deficit of visuo-manual guidance, considered as consecutive to ventral and dorsal damage, respectively, has provided the main argument for this dichotomic view. In the first part of this paper, we show that the currently available empirical data do not suffice to support a double-dissociation between OA and VA. In the second part, we review evidence coming from human neuropsychology and monkey data, which cast further doubts on the validity of a simple double-dissociation between perception and action because they argue for a far more complex organisation with multiple parallel visual-to-motor connections: 1. A dorso-dorsal pathway (involving the most dorsal part of the parietal and pre-motor cortices): for immediate visuo-motor control--with OA as typical disturbance. The latest research about OA is reviewed, showing how these patients exhibit deficits restricted to the most direct and fast visuo-motor transformations. We also propose that mild mirror ataxia, consisting of misreaching errors when the controlesional hand is guided to a visual goal though a mirror, could correspond to OA with an isolated "hand effect". 2. A ventral stream-prefrontal pathway (connections from the ventral visual stream to pre-frontal areas, by-passing the parietal areas): for "mediate" control (involving spatial or temporal transpositions [Rossetti, Y., & Pisella, L. (2003). Mediate responses as direct evidence for intention: Neuropsychology of Not to-, Not now- and Not there-tasks. In S. Johnson (Ed.), Cognitive Neuroscience perspectives on the problem of intentional action (pp. 67-105). MIT Press.])--with VA as typical disturbance. Preserved visuo-manual guidance in patients with VA is restricted to immediate goal-directed guidance, they exhibit deficits for delayed or pantomimed actions. 3. A ventro-dorsal pathway (involving the more ventral part of the parietal lobe and the pre-motor and pre-frontal areas): for complex planning and programming relying on high representational levels with a more bilateral organisation or an hemispheric lateralisation--with mirror apraxia, limb apraxia and spatial neglect as representatives. Mirror apraxia is a deficit that affects both hands after unilateral inferior parietal lesion with the patients reaching systematically and repeatedly toward the virtual image in the mirror. Limb apraxia is localized on a more advanced conceptual level of object-related actions and results from deficient integrative, computational and "working memory" capacities of the left inferior parietal lobule. A component of spatial working memory has recently been revealed also in spatial neglect consecutive to lesion involving the network of the right inferior parietal lobule and the right frontal areas. We conclude by pointing to the differential temporal constraints and integrative capabilities of these parallel visuo-motor pathways as keys to interpret the neuropsychological deficits.

Neural activity related to self- versus externally generated painful stimuli reveals distinct differences in the lateral pain system in a parametric fMRI study.

Self-generated sensory stimulation can be distinguished from externally generated stimulation that is otherwise identical. To determine how the brain differentiates external from self-generated noxious stimulation and which structures of the lateral pain system use neural signals to predict the sensory consequences of self-generated painful stimulation, we used functional magnetic resonance imaging to examine healthy human subjects who received thermal-contact stimuli with noxious and non-noxious temperatures on the resting right hand in random order. These stimuli were internally (self-generated) or externally generated. Two additional conditions served as control conditions: to account for stimulus onset uncertainty, acoustic stimuli preceding the same thermal stimuli were used with variable or fixed delays but without any stimulus-eliciting movements. Whereas graded pain-related activity in the insula and secondary somatosensory cortex (SII) was independent of how the stimulus was generated, it was attenuated in the primary somatosensory cortex (SI) during self-generated stimulation. These data agree with recent concepts of the parallel processing of nociceptive signals to the primary and secondary somatosensory cortices. They also suggest that brain areas that encode pain intensity do not distinguish between internally or externally applied noxious stimuli, i.e., this adaptive biological mechanism prevents harm to the individual. The attenuated activation of SI during self-generated painful stimulation might be a result of the predictability of the sensory consequences of the pain-related action.

Listening to action-related sentences modulates the activity of the motor system: a combined TMS and behavioral study.

Transcranial magnetic stimulation (TMS) and a behavioral paradigm were used to assess whether listening to action-related sentences modulates the activity of the motor system. By means of single-pulse TMS, either the hand or the foot/leg motor area in the left hemisphere was stimulated in distinct experimental sessions, while participants were listening to sentences expressing hand and foot actions. Listening to abstract content sentences served as a control. Motor evoked potentials (MEPs) were recorded from hand and foot muscles. Results showed that MEPs recorded from hand muscles were specifically modulated by listening to hand-action-related sentences, as were MEPs recorded from foot muscles by listening to foot-action-related sentences. This modulation consisted of an amplitude decrease of the recorded MEPs. In the behavioral task, participants had to respond with the hand or the foot while listening to actions expressing hand and foot actions, as compared to abstract sentences. Coherently with the results obtained with TMS, when the response was given with the hand, reaction times were slower during listening to hand-action-related sentences, while when the response was given with the foot, reaction times were slower during listening to foot-action-related sentences. The present data show that processing verbally presented actions activates different sectors of the motor system, depending on the effector used in the listened-to action.

Motor reorganization in asymptomatic carriers of a single mutant Parkin allele: a human model for presymptomatic parkinsonism.

Mutations in the Parkin gene are the most common known single cause of early-onset parkinsonism. It has been shown that asymptomatic carriers with a single mutant allele have latent presynaptic dopaminergic dysfunction in the striatum. Here we used functional MRI to map movement-related neuronal activity during internally selected or externally determined finger movements in 12 asymptomatic carriers of a Parkin mutation and 12 healthy non-carriers. Mean response times were 63 ms shorter during internally selected movements than during externally guided movements (P = 0.003). There were no differences in mean response times between groups (P > 0.2). Compared with externally determined movements, the internal selection of movements led to a stronger activation of rostral motor areas, including the rostral cingulate motor area (rCMA), rostral supplementary motor area, medial and dorsolateral prefrontal cortices. The genotype had a significant impact on movement-related activation patterns. Asymptomatic carriers showed a stronger increase in movement-related activity in the right rCMA and left dorsal premotor cortex, but only if movements relied on internal cues. In addition, synaptic activity in the rCMA had a stronger influence on activity in the basal ganglia in the context of internally selected movements in asymptomatic carriers relative to non-carriers. We infer that this reorganization of striatocortical motor loops reflects a compensatory effort to overcome latent nigrostriatal dysfunction.

[Apraxias]. / Apraxien.

Apraxias are deficits in higher motor behaviour that are not primarily caused by elementary deficits of the sensorimotor system, communication problems, or dementia. These patients present with deficits such as imitating meaningful or meaningless gestures and in dexterity or purposeful use of objects. The different forms of apraxia originate from lesions of different levels/structures of the motor system, reflecting its complexity. Apraxias are caused by deficits in motor programmes generated in the frontal motor areas, in modality-specific higher sensorimotor control, or at the highest level of motor planning and motor conception. The types of apraxia differentially affect activities of daily living and hence show marked differences in the prognosis of recovery and the physiotherapeutic treatment required. Therefore, appropriate diagnosis and treatment of the different forms are of foremost clinical importance.

The anterior cingulate cortex contains distinct areas dissociating external from self-administered painful stimulation: a parametric fMRI study.

The anterior cingulate cortex (ACC) has a pivotal role in human pain processing by integrating sensory, executive, attentional, emotional, and motivational components of pain. Cognitive modulation of pain-related ACC activation has been shown by hypnosis, illusion and anticipation. The expectation of a potentially noxious stimulus may not only differ as to when but also how the stimulus is applied. These combined properties led to our hypothesis that ACC is capable of distinguishing external from self-administered noxious tactile stimulation. Thermal contact stimuli with noxious and non-noxious temperatures were self-administered or externally applied at the resting right hand in a randomized order. Two additional conditions without any stimulus-eliciting movements served as control conditions to account for the certainty and uncertainty of the impending stimulus. Calculating the differences in the activation pattern between self-administered and externally generated stimuli revealed three distinct areas of activation that graded with perceived stimulus intensity: (i) in the posterior ACC with a linear increase during external but hardly any modulation for the self-administered stimulation, (ii) in the midcingulate cortex with activation patterns independent of the mode of application and (iii) in the perigenual ACC with increasing activation during self-administered but decreasing activation during externally applied stimulation. These data support the functional segregation of the human ACC: the posterior ACC may be involved in the prediction of the sensory consequences of pain-related action, the midcingulate cortex in pain intensity coding and the perigenual ACC is related to the onset uncertainty of the impending stimuli.

Cerebellar neural responses related to actively and passively applied noxious thermal stimulation in human subjects: a parametric fMRI study.

Cerebellar activation is consistently found during noxious stimulation but little is known about its pain-related specificity. Under natural circumstances noxious stimuli are actively or passively delivered with concomitant tactile sensory stimulation. Using fMRI we therefore studied pain-related cerebellar activation with innocuous and noxious thermal stimuli in a parametric design taking motor execution as confounding factor into account. With respect to psychophysical pain ratings anterior vermal and ipsilateral hemispheric lobule VI activation was parametrically modulated for stimulus intensity in actively but not in passively elicited thermal stimulation. The cerebellum seems to be capable of distinguishing active from passive painful stimuli.

Left and right superior parietal lobule in tactile object discrimination.

Tactile object discrimination is one of the major manual skills of humans. While the exploring finger movements are not perceived explicitly, attention to the movement-evoked kinaesthetic information gates the tactile perception of object form. Using event-related functional magnetic resonance imaging in seven healthy subjects we found one area in the right superior parietal cortex, which was specifically activated by kinaesthetic attention during tactile object discrimination. Another area with similar location in the left hemisphere was related to the maintenance of tactile information for subsequent object discrimination. We conclude that kinaesthetic information is processed in the anterior portion of the superior parietal cortex (aSPL) with a right hemispheric predominance for discrimination and a left hemispheric predominance for information maintenance.

Cerebellar activation in opsoclonus: an fMRI study.

It is controversial whether opsoclonus is a cerebellar or brainstem disorder. Two patients whose opsoclonus largely disappeared on eye closure underwent fMRI. A comparison of these two states revealed neither vermal nor brainstem activation but rather a bilateral activation in the deep cerebellar nuclei in excess of what the authors found in healthy subjects. The results support a crucial role of the fastigial nucleus in opsoclonus.

Neural activity in human primary motor cortex areas 4a and 4p is modulated differentially by attention to action.

The mechanisms underlying attention to action are poorly understood. Although distracted by something else, we often maintain the accuracy of a movement, which suggests that differential neural mechanisms for the control of attended and nonattended action exist. Using functional magnetic resonance imaging (fMRI) in normal volunteers and probabilistic cytoarchitectonic maps, we observed that neural activity in subarea 4p (posterior) within the primary motor cortex was modulated by attention to action, while neural activity in subarea 4a (anterior) was not. The data provide the direct evidence for differential neural mechanisms during attended and unattended action in human primary motor cortex.