Dopamine boosts intention and action awareness in Parkinson’s disease

Dopaminergic deficiency in Parkinson’s disease (PD) has been associated with underactivation of the supplementary motor area and a reduction of voluntary actions. In these patients, awareness of intention to act has been shown to be delayed. However, delayed awareness of intention to act has also been shown in patients with hyperdopaminergic states and an excess of unwilled movements, as in Tourette’s, and in patients with functional movement disorders. Hence, the role of dopamine in the awareness of intention and action remains unclear. 36 PD patients were tested ON and OFF dopaminergic medication and compared with 35 healthy age-matched controls. In addition, 17 PD patients with subthalamic deep brain stimulation (DBS) were tested ON medication and ON and OFF stimulation. Participants judged either the moment a self-generated action was performed, or the moment the urge to perform the action was felt, using the “Libet method”. Temporal judgments of intention and action awareness were comparable between unmedicated PD patients and controls. Dopaminergic medication boosted anticipatory awareness of both intentions and actions in PD patients, relative to an unmedicated condition. The difference between ON/OFF DBS was not statistically reliable. Functional improvement of motor ability in PD through dopaminergic supplementation leads to earlier awareness of both intention, and of voluntary action

Clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic ischemic lesions

Purpose: Lacunar infarcts are thought to result from occlusion of small penetrating arteries due to microatheroma and lipohyalinosis, pathognomonic for cerebral small vessel disease (CSVD). Concurrent embolic ischemic lesions indicate a different stroke mechanism. The purpose of this study was to examine the clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic infarcts on diffusion-weighted imaging (DWI). Methods: All patients screened for the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290) were reviewed for acute lacunar infarcts and concurrent embolic lesions on baseline DWI. Clinical characteristics and outcome were compared between lacunar infarct patients with and without concurrent embolic lesions. Results: Of 244 patients with an acute lacunar infarct, 20 (8.2%) had concurrent acute embolic infarcts. Compared to patients with a lacunar infarct only, patients with concurrent embolic infarcts were older (mean age 69 years vs. 63 years; p = 0.031), more severely affected (median National Institutes of Health Stroke Scale [NIHSS] score 5 vs. 4; p = 0.046), and—among those randomized—had worse functional outcome at 90 days (median modified Rankin Scale [mRS] 3 vs. 1; p = 0.011). Conclusion: Approximately 8% of lacunar infarct patients show concurrent embolic lesions suggesting a stroke etiology other than CSVD. These patients are more severely affected and have a worse functional outcome illustrating the need for a thorough diagnostic work-up of possible embolic sources even in patients with an imaging-defined diagnosis of lacunar infarcts

Mechanism of action of pallidal deep brain stimulation in patients with dystonia

Die pallidale tiefe Hirnstimulation (THS) bei Patienten mit einer schweren, medikamentös unzureichend behandelbaren Dystonie ist eine gut etablierte Therapie, die zu einer außerordentlichen Verbesserung der motorischen Beschwerden führt. Der genaue Wirkmechanismus ist jedoch bis heute nicht endgültig verstanden. Aus elektrophysiologischen Untersuchungen ist bekannt, dass Aufnahmen pallidaler lokaler Feldpotentiale (LFP) bei Patienten mit Dystonie erhöhte synchrone Oszillationen im niedrigfrequenten Bereich (4-12 Hz) zeigen, die insbesondere mit phasischen dystonen Bewegungen kohärent sind. Folglich wird vermutet, dass pallidale THS zu einer Verminderung dieser pathologisch erhöhten Oszillationen innerhalb des kortiko-basalen Netzwerkes und somit zu einer Abnahme der unwillkürlichen Muskelkontraktionen führt. In der vorliegenden Arbeit wurden pallidale LFP aus 16 Hemisphären von 12 Patienten mit unterschiedlichen Formen einer Dystonie, die sich einer THS unterzogen, untersucht. Unter Verwendung eines speziell angefertigten Vorverstärkers, konnten erstmalig LFP unter laufender pallidaler, hochfrequenter Stimulation (HFS) abgeleitet werden. Das parallele Aufzeichnen von EEG-Aktivität über motorischen Kortexarealen und EMG-Aktivität aus betroffenen Halsmuskeln vor und im Anschluss an die pallidale HFS ermöglichte, über Berechnungen von Kohärenzen, die Untersuchung des Stimulationseffektes innerhalb des kortiko-basalen Netzwerkes. Unsere Ergebnisse zeigen, dass pallidale HFS zu einer signifikanten Abnahme der mittleren 4-12 Hz Aktivität um bis zu 24.8 ± 7.0% bei Patienten mit vorrangig phasischen dystonen Bewegungen führte. Ferner war innerhalb der ersten 30 s nach Stimulationsende auch eine signifikante Abnahme der LFP-EEG Kohärenzen im Bereich von 4-12 Hz nachweisbar. LFP-EMG Kohärenzen wurden hauptsächlich bei Patienten mit phasischen dystonen Bewegungen beobachtet und waren unmittelbar nach HFS ebenfalls unterdrückt. Wir konnten demonstrieren, dass HFS zu einer Suppression der pathologisch erhöhten niedrigfrequenten pallidalen Aktivität bei Patienten mit phasischen dystonen Bewegungen führen kann. Diese phasischen dystonen Komponenten scheinen am schnellsten auf HFS anzusprechen, sodass sie mit der direkten Modulation pathologischer Basalganglien-Aktivität assoziiert werden können. Demgegenüber scheint die Verbesserung der tonischen dystonen Bewegungen von längerfristigen HFS-induzierten plastischen Veränderungen im kortiko-basalen Netzwerk abhängig zu sein, vergleichbar mit dem verzögerten klinischen Wirkeffekt.Pallidal deep brain stimulation (DBS) is a well-established and highly reliable therapy for severe, medically refractory dystonia, which markedly improves motor symptoms. However, the predictors of clinical outcome are not well known and the precise mechanism of action is still not entirely understood. Electrophysiological studies in patients with dystonia have revealed evidence for disease-specific enhanced low frequency activity (4-12 Hz) in pallidal local field potential (LFP) recordings causing characteristic dystonic movements. One hypothesis posits that disruption of abnormally enhanced low frequency activity may thus represent one of the potential mechanisms of DBS. Our aim was to assess whether pallidal high-frequency stimulation (HFS) suppresses local activity, and, if so, whether this effect is propagated along the basal ganglia-motor cortical network to reduce involuntary movements. To explore this, pallidal LFPs were recorded from DBS electrodes implanted in 16 hemispheres of 12 dystonia patients using a specially designed amplifier that allows simultaneous monopolar high-frequency stimulation (HFS) at therapeutic parameter settings and LFP recordings of the same target. For coherence analysis EEG activity over motor areas and EMG activity from affected neck muscles were recorded before and immediately after cessation of HFS. In line with previous studies we were able to confirm the presence of enhanced low frequency activity (4-12 Hz) in all patients with dystonia. Moreover, we could show that HFS led to a significant reduction of mean LFP activity at frequencies between 4 and 12 Hz by 24.8 ± 7.0% in patients with predominantly phasic dystonic movements. In addition, a significant decrease of EEG-LFP coherence in the 4-12 Hz range was revealed for the time period of 30 s after switching off HFS. EMG-LFP coherence was mainly found in patients with phasic dystonic movements showing a peak in the 4-12 Hz range, which likewise was suppressed after HFS. We conclude that HFS may show immediate effects on local synchronized pallidal activity in patients with phasic dystonia as well as modulation of network activity to motor cortical areas and dystonic muscles. It could be speculated that frequency- specific suppression of 4-12 Hz activity by pallidal HFS may directly be related to the reduction of phasic dystonic movements that are known to be the quickest to respond to HFS. In contrast, amelioration of tonic dystonic features may depend on long-term plastic changes at multiple levels of the basal ganglia-motor cortical network similar to the delayed clinical improvement

Effect of Intravenous Alteplase on Functional Outcome and Secondary Injury Volumes in Stroke Patients with Complete Endovascular Recanalization

Intravenous thrombolytic therapy with alteplase (IVT) is a standard of care in ischemic stroke, while recent trials investigating direct endovascular thrombectomy (EVT) approaches showed conflicting results. Yet, the effect of IVT on secondary injury volumes in patients with complete recanalization has not been analyzed. We hypothesized that IVT is associated with worse functional outcome and aggravated secondary injury volumes when administered to patients who subsequently attained complete reperfusion after EVT. Anterior circulation ischemic stroke patients with complete reperfusion after thrombectomy defined as thrombolysis in cerebral infarctions (TICI) scale 3 after thrombectomy admitted between January 2013–January 2021 were analyzed. Primary endpoints were the proportion of patients with functional independence defined as modified Rankin Scale (mRS) score 0–2 at day 90, and secondary injury volumes: Edema volume in follow-up imaging measured using quantitative net water uptake (NWU), and the rate of symptomatic intracerebral hemorrhage (sICH). A total of 219 patients were included and 128 (58%) patients received bridging IVT before thrombectomy. The proportion of patients with functional independence was 28% for patients with bridging IVT, and 34% for patients with direct thrombectomy (p = 0.35). The rate of sICH was significantly higher after bridging IVT (20% versus 7.7%, p = 0.01). Multivariable logistic and linear regression analysis confirmed the independent association of bridging IVT with sICH (aOR: 2.78, 95% CI: 1.02–7.56, p = 0.046), and edema volume (aOR: 8.70, 95% CI: 2.57–14.85, p = 0.006). Bridging IVT was associated with increased edema volume and risk for sICH as secondary injury volumes. The results of this study encourage direct EVT approaches, particularly in patients with higher likelihood of successful EVT

Patient-reported quality of life after intravenous alteplase for stroke in the WAKE-UP trial

Background and Objectives: Intravenous alteplase improves functional outcome after acute ischemic stroke. However, little is known about the effects on self-reported health-related quality of life (HRQoL). Methods: WAKE-UP was a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in stroke with unknown onset time. HRQoL was assessed using the EQ-5D questionnaire at 90 days, comprising the EQ-5D index and the EQ visual analogue scale (VAS). Functional outcome was assessed by the modified Rankin Scale (mRS). We calculated the effect of treatment on EQ-5D index and EQ VAS using multiple linear regression models. Mediation analysis was performed on stroke survivors to explore the extent to which the effect of alteplase on HRQoL was mediated by functional outcome. Results: Among 490 stroke survivors, the EQ-5D index was available for 452 (92.2%), of whom 226 (50%) were assigned to treatment with alteplase and 226 (50%) to placebo. At 90 days, mean EQ-5D index was higher, reflecting a better health state, in patients randomized to treatment with alteplase than with placebo (0.75 vs. 0.67) with an adjusted mean difference of 0.07 (95% CI 0.02-0.12, P=0.005). Also mean EQ VAS was higher with alteplase than with placebo (72.6 vs. 64.9), with an adjusted mean difference of 7.6 (95% CI 3.9-11.8, P<0.001). 85% of the total treatment effect of alteplase on the EQ-5D index was mediated via the mRS score, while there was no significant direct effect. In contrast, the treatment effect on the EQ VAS was mainly via the direct pathway (60%), whereas 40% was mediated by the mRS. Discussion: Assessment of patient-reported outcome measures reveals a potential benefit of intravenous alteplase for HRQoL beyond improvement of functional outcome

Association of white blood cell count with clinical outcome independent of treatment with alteplase in acute ischemic stroke

Introduction: Higher white blood cell (WBC) count is associated with poor functional outcome in acute ischemic stroke (AIS). However, little is known about whether the association is modified by treatment with intravenous alteplase. Methods: WAKE-UP was a randomized controlled trial of the efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in unknown onset stroke. WBC count was measured on admission and again at 22–36 h after randomization to treatment (follow-up). Favorable outcome was defined by a score of 0 or 1 on the modified Rankin scale (mRS) 90 days after stroke. Further outcome were stroke volume and any hemorrhagic transformation (HT) that were assessed on follow-up CT or MRI. Multiple logistic regression analysis was used to assess the association between outcome and WBC count and treatment group. Results: Of 503 randomized patients, WBC count and baseline parameters were available in 437 patients (μ = 64.7 years, 35.2% women) on admission and 355 patients (μ = 65.1 years, 34.1% women) on follow-up. Median WBC count on admission was 7.6 × 109/L (interquartile range, IQR, 6.1–9.4 × 109/L) and 8.2 × 109/L (IQR, 6.7–9.7 × 109/L) on follow-up. Higher WBC count both on admission and follow-up was associated with lower odds of favorable outcome, adjusted for age, National Institutes of Health (NIH) Stroke Scale Score, temperature, and treatment (alteplase vs. placebo, adjusted odds ratio, aOR 0.85, 95% confidence interval [CI] 0.78–0.94 and aOR 0.88, 95% CI 0.79–0.97). No interaction between WBC count and treatment group was observed (p = 0.11). Furthermore, WBC count on admission and follow-up was significantly associated with HT (aOR 1.14, 95% CI 1.05–1.24 and aOR 1.13, 95% CI 1.00–1.26). Finally, WBC count on follow-up was associated with larger stroke volume (aOR 2.57, 95% CI 1.08–6.07). Conclusion: Higher WBC count is associated with unfavorable outcome, an increased risk of HT, and larger stroke volume, independent of treatment with alteplase. Whether immunomodulatory manipulation of WBC count improves stroke outcome needs to be tested. Trial Registration: ClinicalTrials.gov Identifier: NCT01525290

24-hour blood pressure variability and treatment effect of intravenous alteplase in acute ischaemic stroke

Introduction: To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke. Patients and methods: In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke. Results: BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76–4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43–2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26–7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34–2.10) in in the highest quintile. Conclusions: There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis. ClinicalTrials.gov identifier NCT01525290

Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial

International audienceBACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are the most prominent imaging feature of cerebral small vessel disease (cSVD). Previous studies suggest a link between cSVD burden and intracerebral hemorrhage and worse functional outcome after thrombolysis in acute ischemic stroke. We aimed to determine the impact of WMH burden on efficacy and safety of thrombolysis in the MRI-based randomized controlled WAKE-UP trial of intravenous alteplase in unknown onset stroke. METHODS: The design of this post hoc study was an observational cohort design of a secondary analysis of a randomized trial. WMH volume was quantified on baseline fluid-attenuated inversion recovery images of patients randomized to either alteplase or placebo in the WAKE-UP trial. Excellent outcome was defined as score of 0-1 on the modified Rankin Scale after 90 days. Hemorrhagic transformation was assessed on follow-up imaging 24-36 hours after randomization. Treatment effect and safety were analyzed by fitting multivariable logistic regression models. RESULTS: Quality of scans was sufficient in 441 of 503 randomized patients to delineate WMH. Median age was 68 years, 151 patients were female, and 222 patients were assigned to receive alteplase. Median WMH volume was 11.4 mL. Independent from treatment, WMH burden was statistically significantly associated with worse functional outcome (odds ratio, 0.72 [95% CI, 0.57-0.92]), but not with higher chances of any hemorrhagic transformation (odds ratio, 0.78 [95% CI, 0.60-1.01]). There was no interaction of WMH burden and treatment group for the likelihood of excellent outcome (P=0.443) or any hemorrhagic transformation (P=0.151). In a subgroup of 166 patients with severe WMH, intravenous thrombolysis was associated with higher odds of excellent outcome (odds ratio, 2.40 [95% CI, 1.19-4.84]) with no significant increase in the rate of hemorrhagic transformation (odds ratio, 1.96 [95% CI, 0.80-4.81]). CONCLUSIONS: Although WMH burden is associated with worse functional outcome, there is no association with treatment effect or safety of intravenous thrombolysis in patients with ischemic stroke of unknown onset. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01525290

Clinical Characteristics and Outcome of Patients with Lacunar Infarcts and Concurrent Embolic Ischemic Lesions

PURPOSE: Lacunar infarcts are thought to result from occlusion of small penetrating arteries due to microatheroma and lipohyalinosis, pathognomonic for cerebral small vessel disease (CSVD). Concurrent embolic ischemic lesions indicate a different stroke mechanism. The purpose of this study was to examine the clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic infarcts on diffusion-weighted imaging (DWI). METHODS: All patients screened for the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290) were reviewed for acute lacunar infarcts and concurrent embolic lesions on baseline DWI. Clinical characteristics and outcome were compared between lacunar infarct patients with and without concurrent embolic lesions. RESULTS: Of 244 patients with an acute lacunar infarct, 20 (8.2%) had concurrent acute embolic infarcts. Compared to patients with a lacunar infarct only, patients with concurrent embolic infarcts were older (mean age 69 years vs. 63 years; p = 0.031), more severely affected (median National Institutes of Health Stroke Scale [NIHSS] score 5 vs. 4; p = 0.046), and-among those randomized-had worse functional outcome at 90 days (median modified Rankin Scale [mRS] 3 vs. 1; p = 0.011). CONCLUSION: Approximately 8% of lacunar infarct patients show concurrent embolic lesions suggesting a stroke etiology other than CSVD. These patients are more severely affected and have a worse functional outcome illustrating the need for a thorough diagnostic work-up of possible embolic sources even in patients with an imaging-defined diagnosis of lacunar infarcts.status: publishe