Intravenous levetiracetam in clinical practice--Results from an independent registry.

PURPOSE: Most common clinical studies with antiepileptic drugs do not reflect medical everyday practice due to their strict in- and exclusion criteria and specifications of treatment regimens. Here we present a large non-interventional registry with the intention to evaluate the spectrum of applications in daily use and the efficacy and tolerability of intravenously given levetiracetam (LEV-iv). METHODS: In a prospective approach of 17 neurological and neuropediatric centres in Germany LEV-iv treated patients of all ages were included over a period of 10 months. The observational period was 10 days with daily documentation of LEV-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events (AEs). In addition, treatment efficacy and tolerability were assessed by patients and physicians at study end as well as practicability of LEV-iv using a five-step scale. RESULTS: In 95 patients LEV-iv was administered, 93 were included into the analysis. The median LEV-iv dose was 1500 mg (range 110-6000 mg) per day. Median age was 66 years (range 0.7-90.3 years). The majority of patients (n=70, 75%) suffered from status epilepticus (SE, n=55, 59%) and acute seizure clusters (n=15, 16%). Of those with SE, 41 patients (75%) had SE for the first time. Acute seizure clusters and SE terminated in 83% after LEV-iv administration. A total of 29 adverse events were reported in 17 of the 95 patients from the safety set. Ten of these were at least possibly related to LEV-iv treatment. Slight decrease of blood pressure during the infusion (3 patients each) was captured most frequently. No serious side effect was observed. Physicians rated the efficacy and tolerability of LEV-iv treatment as good or very good in 78% and 82% of the cases, respectively. CONCLUSION: In this large observational study of everyday practise the use of LEV-iv exhibited a remarkable good response and tolerability in patients with acute onset seizures (mostly SE). Further randomized controlled studies, like the established status epilepticus trial (ESET) are needed to confirm these findings.

Reasoning about the implications of facial expressions: a behavioral and fMRI study on low and high social impact.

Inferring the cause of another person's emotional state is relevant for guiding behavior in social interactions. With respect to their potentially evoked behavioral reactions some emotional states like anger or happiness are considered to have high social impact while others such as fear and sadness have low social impact. We conducted a functional magnetic resonance imaging study to map the brain activation patterns related to reasoning about facial expressions of emotions with high or low social impact in twenty-six healthy volunteers with good emotional competence, self-reported empathy, and explicit facial affect recognition abilities. Our data show that empathic reasoning was faster and more accurate for high impact emotional states than for low impact emotional states. Activated brain areas involved brain circuits associated with basic and higher order empathy and decision-making in the dorsomedial and dorsolateral frontal cortex. However, activation in higher order areas was less during reasoning about emotional states of high social impact. Taken together, reasoning of high and low impact emotional states relied on similar empathy-related brain areas with reasoning about emotional states of low social impact being more erroneous and requiring more cognitive resources.

Processing of subliminal facial expressions of emotion: a behavioral and fMRI study.

The recognition of emotional facial expressions is an important means to adjust behavior in social interactions. As facial expressions widely differ in their duration and degree of expressiveness, they often manifest with short and transient expressions below the level of awareness. In this combined behavioral and fMRI study, we aimed at examining whether or not consciously accessible (subliminal) emotional facial expressions influence empathic judgments and which brain activations are related to it. We hypothesized that subliminal facial expressions of emotions masked with neutral expressions of the same faces induce an empathic processing similar to consciously accessible (supraliminal) facial expressions. Our behavioral data in 23 healthy subjects showed that subliminal emotional facial expressions of 40 ms duration affect the judgments of the subsequent neutral facial expressions. In the fMRI study in 12 healthy subjects it was found that both, supra- and subliminal emotional facial expressions shared a widespread network of brain areas including the fusiform gyrus, the temporo-parietal junction, and the inferior, dorsolateral, and medial frontal cortex. Compared with subliminal facial expressions, supraliminal facial expressions led to a greater activation of left occipital and fusiform face areas. We conclude that masked subliminal emotional information is suited to trigger processing in brain areas which have been implicated in empathy and, thereby in social encounters.

A functional magnetic resonance imaging study of visuomotor processing in a virtual reality-based paradigm: Rehabilitation Gaming System.

The Rehabilitation Gaming System (RGS) has been designed as a flexible, virtual-reality (VR)-based device for rehabilitation of neurological patients. Recently, training of visuomotor processing with the RGS was shown to effectively improve arm function in acute and chronic stroke patients. It is assumed that the VR-based training protocol related to RGS creates conditions that aid recovery by virtue of the human mirror neuron system. Here, we provide evidence for this assumption by identifying the brain areas involved in controlling the catching of approaching colored balls in the virtual environment of the RGS. We used functional magnetic resonance imaging of 18 right-handed healthy subjects (24 ± 3 years) in both active and imagination conditions. We observed that the imagery of target catching was related to activation of frontal, parietal, temporal, cingulate and cerebellar regions. We interpret these activations in relation to object processing, attention, mirror mechanisms, and motor intention. Active catching followed an anticipatory mode, and resulted in significantly less activity in the motor control areas. Our results provide preliminary support for the hypothesis underlying RGS that this novel neurorehabilitation approach engages human mirror mechanisms that can be employed for visuomotor training.

The neural correlates of affect reading: an fMRI study on faces and gestures.

As complex social beings, people communicate, in addition to spoken language, also via nonverbal behavior. In social face-to-face situations, people readily read the affect and intentions of others in their face expressions and gestures recognizing their meaning. Importantly, the addressee further has to discriminate the meanings of the seen communicative motor acts in order to be able to react upon them appropriately. In this functional magnetic resonance imaging study 15 healthy non-alexithymic right-handers observed video-clips that showed the dynamic evolution of emotional face expressions and gestures evolving from a neutral to a fully developed expression. We aimed at disentangling the cerebral circuits related to the observation of the incomplete and the subsequent discrimination of the evolved bodily expressions of emotion which are typical for everyday social situations. We show that the inferior temporal gyrus and the inferior and dorsal medial frontal cortex in both cerebral hemispheres were activated early in recognizing faces and gestures, while their subsequent discrimination involved the right dorsolateral frontal cortex. Interregional correlations showed that the involved regions constituted a widespread circuit allowing for a formal analysis of the seen expressions, their empathic processing and the subjective interpretation of their contextual meanings. Right-left comparisons revealed a greater activation of the right dorsal medial frontal cortex and the inferior temporal gyrus which supports the notion of a right hemispheric dominance for processing affective body expressions. These novel data provide a neurobiological basis for the intuitive understanding of other people which is relevant for socially appropriate decisions and intact social functioning.

Peripheral blood levels of matrix metalloproteinase-9 predict lesion volume in acute stroke.

Matrix metalloproteinases (MMPs) have been implicated to play an important role in the destruction of the extracellular matrix in diseases of the central nervous system. This study investigated whether the expression of one of these proteases, MMP-9 in blood, is related to the size of human brain infarcts assessed with magnetic resonance imaging. Consecutively, twenty-one acute stroke patients were included prospectively into our study. In blood samples drawn within 24 h after onset, MMP-9 RNA-expression and proteolytic-activity were analyzed by quantitative polymerase chain reaction and gelatin zymography, respectively. The ischemic lesion volumes in time to peak perfusion maps and diffusion weighted imaging were measured morphometrically. RNA-expression levels of MMP-9 in peripheral blood mononuclear cells (PBMCs) correlated with the brain infarct lesion (TTP-delay 4 s, r = -0.61, p = 0.007; TTP-delay 6 s: r = -0.58, p = 0.012; DWI r = -0.47; p = 0.047). Our preliminary results demonstrate that MMP-9 RNA is upregulated in PBMCs in proportion to ischemia. These findings suggest that MMP-9 might contribute to the manifestation of ischemic brain damage. Since MMP-9 is upregulated in acute ischemia inhibition of MMP-9 may represent a complementary treatment target in acute stroke therapy.

Diversity of the inferior frontal gyrus--a meta-analysis of neuroimaging studies.

PURPOSE: The inferior frontal gyrus (IFG) has attracted a lot of interest due to its involvement in motor control and language processing. More recently, it has also been implicated for the processing of empathy. The aim of this meta-analysis was to investigate if neuroimaging studies in humans reveal distinct foci related to empathy as compared to those in motor and speech control in the IFG. MATERIALS AND METHODS: We reviewed MEDLINE for functional imaging studies on healthy subjects published between 1991 and 2007. With the search terms "inferior frontal gyrus", and "statistical parametric mapping" 485 studies were identified. We performed a non-hierarchical cluster-centre analysis of the stereotactic coordinates of the reported 1042 significant activation peaks and investigated seven functional categories using a score of specificity (SCSP). RESULTS: We found four significant, spatially distinct clusters. Three left-hemispheric clusters included one for processing of empathy, one closely adjacent for semantic and phonological processing, and one for working memory, while one cluster for fine movement control was located in the right hemisphere. CONCLUSIONS: This meta-analysis demonstrates a spatio-functional diversity of the left human IFG for processing of language, working memory and empathy. Notably, phonological and semantic processing collapsed into one cluster. Fine movement control located in a cluster in the right IFG occurred in a virtually mirror-like location to processing of empathy in the left hemisphere. These observations are in accordance with the notion of the mirror neuron system mediating specialized links between perception and action.

Alexithymia and impaired facial affect recognition in multiple sclerosis.

Despite the high relevance of emotion processing for social functioning, the study of the impairment of facial affect in multiple sclerosis (MS) has received little attention. Previous research reported evidence for emotion processing deficits but the nature and extent are not fully explained. Thirty-five MS patients underwent dedicated neuropsychological assessment of emotion processing using two facial affect recognition tasks and self-report measures of alexithymia. For comparison, healthy participants served as controls. Relative to healthy controls, MS patients were impaired in facial affect recognition on four of the six Ekman basic emotions, except happiness and disgust. The MS patients were more alexithymic than the healthy controls. These data provide evidence for deficits in the recognition of emotional face expressions and emotional introspection.

Clinical impact of MRI perfusion disturbances and normal diffusion in acute stroke patients.

PURPOSE: In acute ischemic stroke MR-imaging typically shows diffusion abnormalities surrounded by reduced perfusion signifying the so-called ischemic penumbra. Mismatch between diffusion and perfusion abnormalities gives indication for thrombolysis. But is there an indication for thrombolytic treatment, if there is no diffusion abnormality but pathologic perfusion combined with acute stroke symptoms?. MATERIAL AND METHODS: MR-imaging of 1465 patients treated on our Stroke Unit between June 2004 and May 2007 retrospectively are analyzed. 6 patients met the inclusion criteria of severe neurological symptoms, large territorial perfusion disturbances, lack of diffusion abnormalities and complete neurological recovery after treatment. RESULTS: In all six patients MTT measurements showed a significantly depressed perfusion in the symptomatic hemisphere (p<0.02). Time-to-peak delay correlated with the mean transit time delay (0.949, p<0.01). Indication for thrombolysis was based on perfusion abnormalities and clinical symptoms. Stroke symptoms could be reversed in all patients without any complication. CONCLUSION: Whereas diffusion imaging could not reveal any abnormality, perfusion analysis legitimated therapy with systemic thrombolysis in heavily affected patients. This work underlines the importance of multimodal MR imaging for guiding treatment decisions in acute stroke patients.

Valuating other people's emotional face expression: a combined functional magnetic resonance imaging and electroencephalography study.

Reading the facial expression of other people is a fundamental skill for social interaction. Human facial expressions of emotions are readily recognized but may also evoke the same experiential emotional state in the observer. We used event-related functional magnetic resonance imaging and multi-channel electroencephalography to determine in 14 right-handed healthy volunteers (29+/-6 years) which brain structures mediate the perception of such a shared experiential emotional state. Statistical parametric mapping showed that an area in the dorsal medial frontal cortex was specifically activated during the perception of emotions that reflected the seen happy and sad emotional face expressions. This area mapped to the pre-supplementary motor area which plays a central role in control of behavior. Low resolution brain electromagnetic tomography-based analysis of the encephalographic data revealed that the activation was detected 100 ms after face presentation onset lasting until 740 ms. Our observation substantiates recently emerging evidence suggesting that the subjective perception of an experiential emotional state-empathy-is mediated by the involvement of the dorsal medial frontal cortex.

CT-perfusion imaging of the human brain: advanced deconvolution analysis using circulant singular value decomposition.

According to indicator dilution theory tissue time-concentration curves have to be deconvolved with arterial input curves in order to get valid perfusion results. Our aim was to adapt and validate a deconvolution method originating from magnetic resonance techniques and apply it to the calculation of dynamic contrast enhanced computed tomography perfusion imaging. The application of a block-circulant matrix approach for singular value decomposition renders the analysis independent of tracer arrival time to improve the results.

Different cortical activations during visuospatial attention and the intention to perform a saccade.

Everyday life often necessitates dissociation between our directed attention and the intention to direct our gaze. Accordingly, the differential role of visual and motor related areas in the one or the other process is an issue of an ongoing debate. Here we used functional magnetic resonance imaging to elaborate a differentiation between visuospatial attention and the intention for a horizontal saccade in these cortical areas. Subjects fixated a central target, while they directed their attention to a colored cue in the left or right visual field. Regardless of its location, the color of the cue instructed the direction of the upcoming saccade (intention). The attention to the peripheral cue and the intention to perform the saccade were thus either directed to the same side or to opposite sides. A random effects analysis of the imaging data showed that activation of the early visual cortex and the motion sensitive complex was biased by attention to the contralateral cue, whereas activity of the color sensitive complex was modulated by the stimulus instructing a contraversive saccade. The posterior parietal cortex and the proper supplementary eye field (SEF) were most strongly activated in case of spatially congruent attention and intention. In contrast, activity of the pre-SEF and the frontal eye field was enhanced by spatially divergent attention and intention. The results presented here advance our understanding of how the human brain processes spatial information. Noteworthy, the visuomotor related areas show a subtle cortical separation for visual related attention and saccade related intention.

Visual cortex activation in kinesthetic guidance of reaching.

The purpose of this research was to determine the cortical circuit involved in encoding and controlling kinesthetically guided reaching movements. We used (15)O-butanol positron emission tomography in ten blindfolded able-bodied volunteers in a factorial experiment in which arm (left/right) used to encode target location and to reach back to the remembered location and hemispace of target location (left/right side of midsagittal plane) varied systematically. During encoding of a target the experimenter guided the hand to touch the index fingertip to an external target and then returned the hand to the start location. After a short delay the subject voluntarily moved the same hand back to the remembered target location. SPM99 analysis of the PET data contrasting left versus right hand reaching showed increased (P < 0.05, corrected) neural activity in the sensorimotor cortex, premotor cortex and posterior parietal lobule (PPL) contralateral to the moving hand. Additional neural activation was observed in prefrontal cortex and visual association areas of occipital and parietal lobes contralateral and ipsilateral to the reaching hand. There was no statistically significant effect of target location in left versus right hemispace nor was there an interaction of hand and hemispace effects. Structural equation modeling showed that parietal lobe visual association areas contributed to kinesthetic processing by both hands but occipital lobe visual areas contributed only during dominant hand kinesthetic processing. This visual processing may also involve visualization of kinesthetically guided target location and use of the same network employed to guide reaches to visual targets when reaching to kinesthetic targets. The present work clearly demonstrates a network for kinesthetic processing that includes higher visual processing areas in the PPL for both upper limbs and processing in occipital lobe visual areas for the dominant limb.

Asymptomatic motor cortex displacement due to a giant arachnoid cyst.

Cerebral lesions are held to induce plastic changes of the brain. Less well established, however, is how much space-occupying brain lesions may only displace functional representations. In a 66-year-old man we show, by means of functional magnetic resonance imaging and transcranial magnetic stimulation, a profound displacement of the motor cortex due to a large asymptomatic arachnoid cyst. Thus, the chronically compressed brain is capable of sustaining normal brain function without utilizing the potential of cortical plasticity.

EFNS guideline on neuroimaging in acute stroke. Report of an EFNS task force.

Neuroimaging techniques are necessary for the evaluation of stroke, one of the leading causes of death and neurological impairment in developed countries. The multiplicity of techniques available has increased the complexity of decision making for physicians. We performed a comprehensive review of the literature in English for the period 1965-2005 and critically assessed the relevant publications. The members of the panel reviewed and corrected an initial draft, until a consensus was reached on recommendations stratified according to the European Federation of Neurological Societies (EFNS) criteria. Non-contrast computed tomography (CT) scan is the established imaging procedure for the initial evaluation of stroke patients. However, magnetic resonance imaging (MRI) has a higher sensitivity than CT for the demonstration of infarcted or ischemic areas and depicts well acute and chronic intracerebral hemorrhage. Perfusion and diffusion MRI together with MR angiography (MRA) are very helpful for the acute evaluation of patients with ischemic stroke. MRI and MRA are the recommended techniques for screening cerebral aneurysms and for the diagnosis of cerebral venous thrombosis and arterial dissection. For the non-invasive study of extracranial vessels, MRA is less portable and more expensive than ultrasonography but it has higher sensitivity and specificity for carotid stenosis. Transcranial Doppler is very useful for monitoring arterial reperfusion after thrombolysis, for the diagnosis of intracranial stenosis and of right-to-left shunts, and for monitoring vasospasm after subarachnoid hemorrhage. Currently, single photon emission computed tomography and positron emission tomography have a more limited role in the evaluation of the acute stroke patient.

Quantitative assessment of recovery from motor hemineglect in acute stroke patients.

BACKGROUND AND PURPOSE: Motor hemineglect is characterized by an underutilization of one side of the body. It is a higher-order motor disorder that resembles hemiplegia although being substantially different from it due to a preserved motor output system. Its role for poststroke recovery is still unclear. METHODS: We studied 52 patients presenting with acute hemiparetic stroke over the first 7 days after symptom onset. Nineteen patients had unilateral motor hemineglect. Impairment was clinically assessed with the European Stroke Scale and a multifactorial motor score. It was further assessed quantitatively, as overall arm activity was measured continuously by Actiwatches. Lesion volumes were measured morphometrically within 24 h on perfusion- and diffusion-weighted magnetic resonance images and on average on day 9 by T2-weighted magnetic resonance imaging. RESULTS: Patients with motor hemineglect were characterized by significantly reduced initial arm activity in comparison to patients without motor hemineglect. This was paralleled by larger brain lesions in the patients with motor hemineglect. Patients with motor neglect either recovered virtually completely (5 cases; 2/5 left hemisphere; 3/5 treated with recombinant tissue plasminogen activator, rt-PA) within 7 days or did not improve at all (14 cases; 3/14 left hemisphere; 3/14 rt-PA treated). CONCLUSION: Our data reveal a high incidence of motor hemineglect in patients with acute stroke. They further show that these patients are more severely compromised than those without motor hemineglect. A rapid and near complete recovery was observed in about one fourth of the motor hemineglect patients and may be related to involvement of the left hemisphere or to therapy with thrombolysis.

Reorganization of cerebral circuits in human brain lesion.

Recovery after focal brain lesions is supposed to be mediated by cerebral reorganization. Stroke is a powerful model to study these processes in the human brain, since middle cerebral artery infarction is a common neurological disease with a clearly defined onset of a lateralized sensorimotor deficit syndrome. Brain tumours constitute a further model differing from stroke by their slow lesion dynamics. Evidence from functional neuroimaging and transcranial magnetic stimulation will be presented showing that recovery of hand function is related to reorganization of local perilesional and large-scale circuits involving the contralesional hemisphere.

Cingulate cortex activation and competing responses: the role of preparedness for competition.

Regional cerebral blood flow (rCBF) was studied in a task, where a preparatory stimulus (S1) cued for an imperative second stimulus (S2) which was associated with a response. Two preparatory stimuli cued unequivocally each for one response. In contrast, a third preparatory stimulus cued for two response alternatives which appeared for the same ratio (each in 50% of all trials) introducing response competition. In a first experimental condition, non-arbitrary, unambiguous stimuli were used as S1 to enable the subjects to prepare their responses. In a second and third scan, arbitrary preparatory stimuli were used during different stages of awareness for the S1-S2 association. Subjects performed this task "naive" without knowledge about the S1-S2 association and also in an experimental condition being aware of the S1-S2 association. Button presses after unambiguous, non-arbitrary preparatory stimuli activated the right middle frontal gyrus and inferior parietal lobe if S1 was associated with a definite response. When the subjects did not know the S1-S2 relation, left prefrontal cortex activation was associated with trials including definite responses. Performing the same S1-S2 response condition after subjects knew their relation right prefrontal and left parietal areas became additionally engaged. However, in the first experimental condition using unambiguous, non-arbitrary stimuli and in the third, "aware" experimental condition when S1 was coupled with two response alternatives, the anterior cingulate cortex was activated. As these experimental conditions have in common, that the preparatory stimulus shares information about the upcoming competing response alternatives they highlight the evaluative role of the anterior cingulate cortex for competing actions.

Recruitment of contralesional motor cortex in stroke patients with recovery of hand function.

In neuroimaging studies of stroke patients, coactivation may account for increased recruitment of bilateral motor areas when moving the affected limb. Here we studied eight patients after stroke with fMRI and simultaneous EMG. Bilateral recruitment of premotor and primary motor cortices was evident in five patients with strictly unilateral performance per EMG. Because patients had excellent motor recovery, this increased recruitment suggests an adaptive response to the infarct.

Functional activation within the PI-DWI mismatch region in recovery from ischemic stroke: preliminary observations.

In this study, we sought to investigate if brain tissue affected by ischemia can accommodate areas of activation related to restoration of brain function following ischemic stroke. In two patients perfusion imaging (PI) and diffusion weighted imaging (DWI) obtained in the acute phase after stroke was coregistered with BOLD imaging of brain functions acquired when profound recovery had occurred. Both patients suffered from thrombembolic brain infarction due to dissection of the internal carotid artery (ICA) characterized by a severe PI-DWI mismatch in the acute stage of stroke. Following ICA recanalization and clinical recovery BOLD imaging showed task-specific activation adjacent to the infarct lesion within the former PI-DWI mismatch area. The data in these two stroke patients provide evidence that brain tissue at risk of infarction as shown by the PI-DWI mismatch can survive and, thereby, constitute the major site underlying post-ischemic recovery.