Ten Years of Improving Acute Stroke Management in a Metropolitan Area: A Population-Based Quantification of Quality Indicators.

BACKGROUND AND PURPOSE: Rapid access to acute stroke treatment improves clinical outcomes in patients with ischemic stroke. We aimed to shorten the time to admission and to acute stroke treatment for patients with acute stroke in the Hamburg metropolitan area by collaborative multilevel measures involving all hospitals with stroke units, the Emergency Medical Services (EMS), and health-care authorities. METHODS: In 2007, an area-wide stroke care quality project was initiated. The project included mandatory admission of all stroke patients in Hamburg exclusively to hospitals with stroke units, harmonized acute treatment algorithms among all hospitals, repeated training of the EMS staff, a multimedia educational campaign, and a mandatory stroke care quality monitoring system based on structured data assessment and quality indicators for procedural measures. We analyzed data of all patients with acute stroke who received inhospital treatment in the city of Hamburg during the evaluation period from the quality assurance database data and evaluated trends of key quality indicators over time. RESULTS: From 2007 to 2016, a total of 83,395 patients with acute stroke were registered. During this period, the proportion of patients admitted within ≤3 h from symptom onset increased over time from 27.8% in 2007 to 35.2% in 2016 (p < 0.001). The proportion of patients who received rapid thrombolysis (within ≤30 min after admission) increased from 7.7 to 54.1% (p < 0.001). CONCLUSIONS: Collaborative stroke care quality projects are suitable and effective to improve acute stroke care.

Symmetric dimethylarginine is a marker of detrimental outcome in the acute phase after ischaemic stroke: role of renal function.

Methylarginines have been shown to interfere with NO (nitric oxide) formation by inhibiting NOS (NO synthase)-ADMA (asymmetric dimethylarginine) and cellular L-arginine uptake into the cell [ADMA and SDMA (symmetric dimethylarginine)]. In a recent study, elevation of SDMA was related to long-term mortality in patients recruited 30 days after a stroke event. In the present study, we aimed at investigating the association of SDMA and adverse clinical outcome in the early phase (first 30 days) after acute ischaemic stroke. A total of 137 patients were recruited immediately upon admission to the emergency unit with an acute ischaemic stroke. Plasma levels of methylarginines were determined by a validated LC-MS/MS (liquid chromatography-tandem MS) method. Patients were prospectively followed for 30 days. A total of 25 patients (18.2%) experienced the primary composite endpoint [death, recurrent stroke, MI (myocardial infarction) and rehospitalization]. SDMA plasma levels were significantly higher in stroke patients compared with patients without event (0.89 ± 0.80 compared with 0.51 ± 0.24 µmol/l; P<0.001). SDMA levels were significantly correlated with markers of renal function. Kaplan-Meier survival analysis demonstrated that cumulative survival decreased significantly with ascending tertiles of SDMA (P<0.001). Our study provides the first data indicating that SDMA is strongly associated with adverse clinical outcome during the first 30 days after ischaemic stroke. Our results strengthen the prognostic value of renal function in patients with stroke and confirm the hypothesis that SDMA is a promising marker for renal function.

Early-onset stroke in two siblings with Neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder, characterized by cafe-au-lait macules, benign neurofibromas as well as malignant peripheral nerve sheath tumours, freckling in the axillary or inguinal regions, optic glioma and Lisch nodules (iris hamartomas) and further manifestations like bone deformities etc. Additionally, NF1 patients are at increased risk of early-onset cerebrovascular diseases, the pathogenesis of which has not been clarified yet. Here we report the first case of two siblings with NF1 who suffered an acute ischemic stroke. Professionals treating NF1 patients should be aware of the elevated risk of stroke in this population. Large prospective studies are needed to establish optimal guidelines for diagnosis, monitoring and treatment of cerebrovascular disease in patients suffering from NF1, as well as to achieve a consensus on routine vascular screening in NF1.

Interhemispheric imbalance during visuospatial attention investigated by unilateral and bilateral TMS over human parietal cortices.

We used single-pulse transcranial magnetic stimulation (TMS) to study visuospatial attention. TMS was applied over one hemisphere, or simultaneously over both the right and left posterior parietal cortex (PPC), at two different interstimulus intervals (ISI) during a visual detection task. Unilateral TMS over the right and left PPC, respectively, impaired detection of contralateral presented visual stimuli at an ISI of 150 ms. By contrast, simultaneous biparietal TMS induced no significant changes in correct stimulus detection. TMS at an ISI of 250 ms evoked no changes for magnetic stimulation over either the right or the left parietal cortex. These results suggest that both PPC play a crucial role at a relatively early stage in the widely distributed brain network of visuospatial attention. The abolition of behavioral deficits during simultaneous biparietal TMS underlines the common hypothesis that an interhemispheric imbalance might underlie the disorders of neglect and extinction seen following unilateral brain damage.

Enhancing picture naming with transcranial magnetic stimulation.

The enhancement of cognitive function in healthy subjects by medication, training or intervention yields increasing political, social and ethical attention. In this paper facilitatory effects of single-pulse TMS and repetitive TMS on a simple picture naming task are presented. A significant shortening of picture naming latencies was observed after single-pulse TMS over Wernicke's area. The accuracy of the response was not affected by this speed effect. After TMS over the dominant motor cortex or over the non-dominant temporal lobe, however, no facilitation of picture naming was observed. In the rTMS experiments only rTMS of Wernicke's area had an impact on picture naming latencies resulting in a shortening of naming latencies without affecting the accuracy of the response. rTMS over the visual cortex, Broca's area or over the corresponding sites in the non-dominant hemisphere had no effect. Single-pulse TMS is able to facilitate lexical processes due to a general preactivation of language-related neuronal networks when delivered over Wernicke's area. Repetitive transcranial magnetic stimulation over Wernicke's area also leads to a brief facilitation of picture naming possibly by shortening linguistic processing time. Whether TMS or rTMS can be used to aid linguistic therapy in the rehabilitation phase of aphasic patients should be subject of further investigations.

Role of the posterior parietal cortex in spatial hearing.

The human posterior parietal cortex (PPC) is well known to be involved in various functions of multisensory spatial perception. However, the specific role of the PPC in hearing has, up to now, remained unclear. To allow more reliable conclusions to be drawn on this issue, we have used repetitive transcranial magnetic stimulation in healthy subjects. Focal stimulation of the PPC induced a systematic shift in the lateralization of interaural time differences (ITDs, a main cue for auditory azimuth), whereas the acuity of ITD discrimination was unaffected. We propose that the PPC is specifically involved in relating azimuthal angles of sound to the body coordinates and is part of a "where" stream in cortical processing of auditory information.

Motor cortex hand area and speech: implications for the development of language.

Recently a growing body of evidence has suggested that a functional link exists between the hand motor area of the language dominant hemisphere and the regions subserving language processing. We examined the excitability of the hand motor area and the leg motor area during reading aloud and during non-verbal oral movements using transcranial magnetic stimulation (TMS). During reading aloud, but not before or afterwards, excitability was increased in the hand motor area of the dominant hemisphere. This reading effect was found to be independent of the duration of speech. No such effect could be found in the contralateral hemisphere. The excitability of the leg area of the motor cortex remained unchanged during reading aloud. The excitability during non-verbal oral movements was slightly increased in both hemispheres. Our results are consistent with previous findings and may indicate a specific functional connection between the hand motor area and the cortical language network.

Modulation of a brain-behavior relationship in verbal working memory by rTMS.

We investigated whether the brain-behavior relationship (BBR) between regional cerebral blood flow (rCBF) as measured by positron emission tomography (PET) and individual accuracy in verbal working memory (WM) can be modulated by repetitive transcranial magnetic stimulation (rTMS) of the left or right middle frontal gyrus (MFG). Fourteen right-handed male subjects received a 30-s rTMS train (4 Hz, 110% motor threshold) to the left or right MFG during a 2-back WM task using letters as stimuli. Simultaneously an rCBF PET tracer was injected and whole-brain functional images were acquired. A hypothesis-driven region-of-interest-analysis of the left and right MFG BBR as well as an explorative whole-brain analysis correlating the individual accuracy with rCBF was carried out. Without rTMS we found a negative BBR in the left but no significant BBR in the right MFG. This negative BBR is best explained by an increased effort of volunteers with an inferior task performance. Left-sided rTMS led to a shift of the BBR towards the superior frontal gyrus (SFG) and to a positive BBR in anterior parts of the left SFG. With rTMS of the right MFG the BBR was posterior and inferior in the left inferior frontal gyrus. Beyond the cognitive subtraction approach this correlation analysis provides information on how the prefrontal cortex is involved based on individual performance in working memory. The results are discussed along the idea of a short-term plasticity in an active neuronal network that reacts to an rTMS-induced temporary disruption of two different network modules.

Modification of a functional motor task by non-consciously perceived sensory stimuli.

In recent years it has been suggested that processing of visual information is divided between a ventral stream, responsible for object recognition and conscious processing of object properties, and a dorsal stream mediating automatic integration of visual information into a motor task. We used metacontrast masking to prevent conscious perception of visual cues concerning the load of an object to be lifted in a precision grip. It was found that when such non-consciously perceived cues warned of a load change, they allowed the subjects to produce the grip force profile appropriate to the new load. It is concluded that non-consciously perceived visual information can be utilised to adapt a functional motor task to actual conditions.

Visual cortex excitability increases during visual mental imagery--a TMS study in healthy human subjects.

Previous neuroimaging studies provided evidence that visual mental imagery relies, in part, on the primary visual cortex. We hypothesized that, analogous to the finding that motor imagery increases the excitability of motor cortex, visual imagery should increase visual cortex excitability, as indexed by a decrease in the phosphene threshold (PT). In order to test visual cortex excitability, the primary visual cortex was stimulated with transcranial magnetic stimulation (TMS), so as to elicit phosphenes in the right lower visual quadrant. Subjects performed a visual imagery task and an auditory control task. We applied TMS with increasing intensity to determine the PT for each subject. Independent of the quadrant in which subjects placed their visual images, imagery decreased PT compared to baseline PT; in contrast, the auditory task did not change PT. These findings demonstrate for the first time a short-term, task-dependent modulation of PT. These results constitute evidence that early visual areas participate in visual imagery processing.

Repetitive transcranial magnetic stimulation of the parietal cortex transiently ameliorates phantom limb pain-like syndrome.

OBJECTIVE: Phantom pain is linked to a reorganization of the partially deafferented sensory cortex. In this study we have investigated whether the pain syndrome can be influenced by repetitive transcranial magnetic stimulation (rTMS). METHODS: Two patients with a longstanding unilateral avulsion of the lower cervical roots and chronic pain in the arm were studied. As a control the acute effects of rTMS (15 Hz, 2 s duration) on pain were studied in 4 healthy subjects. Pain intensity was assessed with the Visual Analogue Scale. RESULTS: Stimulation of the contralateral parietal cortex led to a reproducible reduction in pain intensity lasting up to 10 min. Stimulation of other cortical areas produced only minor alterations in the severity of the pain. Both 1 and 10 Hz rTMS trains applied to the contralateral parietal cortex on weekdays for 3 consecutive weeks did, however, not lead to permanent changes in the pain intensity. Experimentally induced pain (cold water immersion of the right hand) in normal subjects was not influenced by rTMS. CONCLUSIONS: These results do not favor the use of rTMS in the treatment of phantom limb pain. The results, however, support the concept that phantom pain is due to a dysfunctional activity in the parietal cortex. The transient rTMS-induced analgesic effect may be due to a temporary interference with the cerebral representation of the deafferented limb.

Visual and motor cortex excitability: a transcranial magnetic stimulation study.

OBJECTIVES: Phosphene thresholds (PTs) to transcranial magnetic stimulation over the occipital cortex and motor thresholds (MTs) have been used increasingly as measures of the excitability of the visual and motor cortex. MT has been utilized as a guide to the excitability of other, non-motor cortical areas such as dorsolateral prefrontal cortex. The aims of this study were to compare the PTs to MTs; to assess their stability across sessions; and to investigate their relation to MTs. METHODS: PTs and MTs were determined using focal transcranial magnetic stimulation over the visual and motor cortex. RESULTS: PTs were shown to be significantly higher than MTs. Both PTs and MTs were stable across sessions. No correlation between PTs and MTs could be established. CONCLUSIONS: Phosphene threshold is a stable parameter of the visual cortex excitability. MTs were not related to the excitability of non-motor cortical areas.

Motor representation in patients rapidly recovering after stroke: a functional magnetic resonance imaging and transcranial magnetic stimulation study.

OBJECTIVE: Neuroimaging studies have suggested an evolution of the brain activation pattern in the course of motor recovery after stroke. Initially poor motor performance is correlated with an recruitment of the uninjured hemisphere that continuously vanished until a nearly normal (contralateral) activation pattern is achieved and motor performance is good. Here we were interested in the early brain activation pattern in patients who showed a good and rapid recovery after stroke. METHODS: Ten patients with first-ever ischemic stroke affecting motor areas had to perform self-paced simple or more complex movements with the affected or the unaffected hand during functional magnetic resonance imaging (fMRI). The location and number of activated voxels above threshold were determined. To study possible changes in the cortical motor output map the amplitude of the motor evoked potentials (MEP) and the extent of the excitable area were determined using transcranial magnetic stimulation (TMS). RESULTS: The pattern of activation observed with movements of the affected and the unaffected hand was similar. In the simple motor task significant (P<0.05) increases were found in the primary motor cortex ipsilateral to the movement, the supplementary motor area and the cerebellar hemisphere contralateral to the movement during performance with the affected hand compared to movements with the unaffected hand. When comparing simple with more complex movements performed with either the affected or the unaffected hand, a further tendency to increased activation in motor areas was observed. The amplitude of MEPs obtained from the affected hemisphere was smaller and the extent of cortical output maps was decreased compared to the unaffected hemisphere; but none of the patients showed MEPs at the affected hand when the ipsilateral unaffected motor cortex was stimulated. CONCLUSIONS: Despite a rapid and nearly complete motor recovery the brain activation pattern was associated with increased activity in (bilateral) motor areas as revealed with fMRI. TMS revealed impaired motor output properties, but failed to demonstrate ipsilateral motor pathways. Successful recovery in our patients may therefore rely on the increased bilateral activation of existing motor networks spared by the injury.

Effects of long-term practice and task complexity in musicians and nonmusicians performing simple and complex motor tasks: implications for cortical motor organization.

Motor practice induces plastic changes within the cortical motor system. Whereas rapidly evolving changes of cortical motor representations were the subject of a number of recent studies, effects of long-term practice on the motor system are so far poorly understood. In the present study pianists and nonmusicians were investigated using functional magnetic resonance imaging. Both groups performed simple and complex movement sequences on a keyboard with the right hand, the tasks requiring different levels of ordinal complexity. The aim of this study was to characterize motor representations related to sequence complexity and to long-term motor practice. In nonmusicians, complex motor sequences showed higher fMRI activations of the presupplementary motor area (pre-SMA) and the rostral part of the dorsal premotor cortex (PMd) compared to simple motor sequences, whereas musicians showed no differential activations. These results may reflect the higher level of visuomotor integration required in the complex task in nonmusicians, whereas in musicians this rostral premotor network was employed during both tasks. Comparison of subject groups revealed increased activation of a more caudal premotor network in nonmusicians comprising the caudal part of the PMd and the supplementary motor area. This supports recent results suggesting a specialization within PMd. Furthermore, we conclude that plasticity due to long-term practice mainly occurs in caudal motor areas directly related to motor execution. The slowly evolving changes in M1 during motor skill learning may extend to adjacent areas, leading to more effective motor representations in pianists.

The neural correlate of very-long-term picture priming.

Repetition priming denotes a behavioural change caused by prior exposure to a stimulus. The effect is known to last for weeks. This study addresses the underlying neural mechanisms for very-long-term picture priming by using event-related functional magnetic resonance imaging complemented by a behavioural paradigm. Previous functional imaging studies with shorter retention intervals have shown that priming is associated with changes in the activity of both the occipital and posterior temporal cortex. In this study we compared retention intervals of 1 day and 6 weeks after initial exposure to a picture stimulus. Priming-related decreases in cortical activity in posterior extrastriate and dorsal left inferior frontal areas were found only for the shorter retention interval. In contrast, fMRI activation in the inferior posterior temporal and anterior left inferior frontal cortex was reduced following priming for both retention intervals. In the behavioural paradigm, the priming effect was stable over time. We conclude that the left inferior frontal and inferior posterior temporal cortex play a key role in the very-long-term priming effect.

Involvement of the superior temporal cortex and the occipital cortex in spatial hearing: evidence from repetitive transcranial magnetic stimulation.

The processing of auditory spatial information in cortical areas of the human brain outside of the primary auditory cortex remains poorly understood. Here we investigated the role of the superior temporal gyrus (STG) and the occipital cortex (OC) in spatial hearing using repetitive transcranial magnetic stimulation (rTMS). The right STG is known to be of crucial importance for visual spatial awareness, and has been suggested to be involved in auditory spatial perception. We found that rTMS of the right STG induced a systematic error in the perception of interaural time differences (a primary cue for sound localization in the azimuthal plane). This is in accordance with the recent view, based on both neurophysiological data obtained in monkeys and human neuroimaging studies, that information on sound location is processed within a dorsolateral "where" stream including the caudal STG. A similar, but opposite, auditory shift was obtained after rTMS of secondary visual areas of the right OC. Processing of auditory information in the OC has previously been shown to exist only in blind persons. Thus, the latter finding provides the first evidence of an involvement of the visual cortex in spatial hearing in sighted human subjects, and suggests a close interconnection of the neural representation of auditory and visual space. Because rTMS induced systematic shifts in auditory lateralization, but not a general deterioration, we propose that rTMS of STG or OC specifically affected neuronal circuits transforming auditory spatial coordinates in order to maintain alignment with vision.

Bilateral parieto-frontal network for verbal working memory: an interference approach using repetitive transcranial magnetic stimulation (rTMS).

Verbal working memory has been attributed to a left-dominant neuronal network, including parietal, temporal and prefrontal cortical areas. The current study was designed to evaluate the contribution of these brain regions to verbal working memory processes and to assess possible hemispheric asymmetry. The effect of repetitive transcranial stimulation (rTMS) on performance in a verbal working memory task both during, and after an rTMS train (110% of individual motor threshold, 4 Hz) over nine different scalp locations was studied [bilateral middle frontal gyrus (MFG), bilateral supramarginal gyrus (SMG), bilateral inferior parietal cortex (IP) and three different midline control sites]. Significant performance deterioration was observed during rTMS over the left and right MFG and left and right IP. There was no consistent interference effect across subjects over the left or right SMG and the three different midline control sites. The interference effect with the given stimulation parameters did not last beyond the rTMS train itself. The data provide evidence for a symmetrical, bilateral parieto-frontal verbal working memory network. The data are discussed with respect to the competing ideas of a parieto-frontal central executive network vs. a network that processes the inherent semantic and object features of the visually presented verbal stimuli in parallel.

Power grip disinhibits the ipsilateral sensorimotor cortex: a TMS and fMRI study.

Electrophysiological studies have shown that forceful activation of the hand muscles (power grip) is accompanied by an increased excitability of the ipsilateral corticospinal system. This increase in excitability may be due to spinal or cortical mechanisms. Here we show with fMRI that this phenomenon is at least in part mediated at a cortical level. We used TMS to show that the increased ipsilateral excitability during a forceful maneuver leads to enhanced stimulus-response curves. fMRI was used to compare the activation during a repetitive hand movement with or without an accompanying power grip on the opposite site. The power grip reduced movement-related activation in the ipsilateral sensorimotor cortex. Peak deactivation was located in the left postcentral gyrus extending into the adjacent precentral gyrus. This finding suggests that a forceful activation of the hand muscles disinhibits a distinct functional representation in the ipsilateral sensorimotor cortex. Consequently, the excitability of the corticospinal system increases and less neuronal excitatory activity is needed to perform a given task. The results may be important for a variety of studies as they suggest that fMRI may show decreased hemodynamic response under conditions in which other neurophysiological methods have shown increased functional activity.