•Intermanual transfer is observed in a sequence learning task, independently of the trained hand's performance.•Pre-training connectivity strength between premotor cortex and nodes within visual ...attention and executive control networks correlates with transfer.•Intermanual transfer is associated with functional connectivity changes within the motor network after training.
Intermanual transfer of motor learning is a form of learning generalization that leads to behavioral advantages in various tasks of daily life. It might also be useful for rehabilitation of patients with unilateral motor deficits. Little is known about neural structures and cognitive processes that mediate intermanual transfer. Previous studies have suggested a role for primary motor cortex (M1) and the supplementary motor area (SMA). Here, we investigated the functional neuroanatomy of intermanual transfer with a special emphasis on functional connectivity within the motor network and between motor regions and attentional networks, including the fronto-parietal executive control network and visual attention networks. We designed a finger tapping task, in which young, heathy subjects trained the non-dominant left hand in the MRI scanner. Behaviorally, transfer of sequence learning was observed in most cases, independently of the trained hand's performance. Pre- and post-training functional connectivity patterns of cortical motor seeds were investigated using generalized psychophysiological interaction analyses. Transfer was correlated with the strength of connectivity between the left premotor cortex and structures within the dorsal attention network (superior parietal cortex, left middle temporal gyrus) and executive control network (right prefrontal regions) during pre-training, relative to post-training. Changes in connectivity within the motor network, and more particularly between trained and untrained M1, as well as between the SMA and untrained M1, correlated with transfer after training. Together, these results suggest that the interplay between attentional, executive and motor networks may support processes leading to transfer, whereas, following training, transfer translates into increased connectivity within the motor network.
In vivo 1H magnetic resonance spectroscopy (1H-MRS) investigations of amyotrophic lateral sclerosis (ALS) mouse brain may provide neurochemical profiles and alterations in association with ALS ...disease progression. We aimed to longitudinally follow neurochemical evolutions of striatum, brainstem and motor cortex of mice transgenic for G93A mutant human superoxide dismutase type-1 (G93A-SOD1), an ALS model. Region-specific neurochemical alterations were detected in asymptomatic G93A-SOD1 mice, particularly in lactate (−19%) and glutamate (+8%) of brainstem, along with γ-amino-butyric acid (−30%), N-acetyl-aspartate (−5%) and ascorbate (+51%) of motor cortex. With disease progression towards the end-stage, increased numbers of metabolic changes of G93A-SOD1 mice were observed (e.g. glutamine levels increased in the brainstem (>+66%) and motor cortex (>+54%)). Through ALS disease progression, an overall increase of glutamine/glutamate in G93A-SOD1 mice was observed in the striatum (p < 0.01) and even more so in two motor neuron enriched regions, the brainstem and motor cortex (p < 0.0001). These 1H-MRS data underscore a pattern of neurochemical alterations that are specific to brain regions and to disease stages of the G93A-SOD1 mouse model. These neurochemical changes may contribute to early diagnosis and disease monitoring in ALS patients.
In the context of motoneuron diseases, gene delivery as an experimental or therapeutic approach is hindered by the challenge to specifically target cell populations that are widely distributed along ...the spinal cord. Further complicating the task, transgenes often need to be delivered to motoneurons and/or glial cells to address the non-cell-autonomous mechanisms involved in disease pathogenesis. Intracerebroventricular (ICV) injection of recombinant adeno-associated viruses (AAVs) in newborn mice allows distributing viral vectors throughout the central nervous system while limiting undesired transduction of peripheral organs. Here, we show that by combining the appropriate set of AAV serotype and promoter, specific transgene expression can be achieved in either motoneurons or astrocytes along the whole mouse spinal cord. ICV injection of recombinant AAV6 with the cytomegalovirus (cmv) promoter preferentially targets motoneurons, whereas AAV9 particles combined with the astrocyte-specific gfaABC₁D promoter lead to significant transgene expression selectively targeted to astrocytes. Importantly, ICV coinjection of both AAV6-cmv and AAV9-gfaABC₁D results in segregated expression of two different transgenes in motoneurons and astrocytes, respectively. Relevance of viral vector delivery via the cerebrospinal fluid was further investigated in young nonhuman primates. Intracisternal injection of recombinant AAV6-cmv led to robust cervical transduction of motoneurons, highlighting the potential of this approach for gene therapy and modeling of motoneuron diseases.
Objective
Amyotrophic lateral sclerosis is an incurable disorder mainly characterized by motoneuron degeneration. Mutations in the superoxide dismutase 1 (SOD1) gene account for 20% of familial forms ...of the disease. Mutant SOD1 exerts multiple pathogenic effects through the gain of toxic properties in both neurons and glial cells. Here, we compare AAV‐based gene therapy suppressing expression of mutant SOD1 in either motoneurons or astrocytes.
Methods
AAV vectors encoding microRNA against human SOD1 were administered to G93ASOD1 mice either by intracerebroventricular injections in pups or by lumbar intrathecal injections in adults. Vector systems were designed to suppress SOD1 expression predominantly in either spinal motoneurons or astrocytes. Electrophysiological and behavioral tests were performed on treated animals to evaluate disease progression.
Results
Following vector injection in G93ASOD1 pups, efficient silencing of SOD1 expression was achieved in motoneurons and/or astrocytes. Most complete protection of motor units was obtained when targeting human SOD1 predominantly in motoneurons. Suppressing SOD1 mainly in astrocytes led to preserved muscle innervation despite only partial protection of spinal motoneurons. In both cases, injection in pups led to full recovery of neuromuscular function and significantly prolonged survival. Vector injections in adult mice also achieved significant protection of neuromuscular function, which was highest when motoneurons were targeted.
Interpretation
These results suggest that AAV‐mediated SOD1 silencing is an effective approach to prevent motoneuron degeneration caused by SOD1 mutation. AAV vectors suppressing SOD1 in motoneurons delay disease onset and show effective neuroprotection. On the other hand, AAV‐based SOD1 silencing in astrocytes rescues neuromuscular function following initial denervation.
Does the brain become more resilient after a first stroke to reduce the consequences of a new lesion? Although recurrent strokes are a major clinical issue, whether and how the brain prepares for a ...second attack is unknown. This is due to the difficulties to obtain an appropriate dataset of stroke patients with comparable lesions, imaged at the same interval after onset. Furthermore, timing of the recurrent event remains unpredictable.
Here, we used a novel clinical lesion simulation approach to test the hypothesis that resilience in brain networks increases during stroke recovery. Sixteen highly selected patients with a lesion restricted to the primary motor cortex were recruited. At 3 time points of the index event (10 days, 3 weeks, 3 months), we mimicked recurrent infarcts by deletion of nodes in brain networks (resting-state functional magnetic resonance imaging). Graph measures were applied to determine resilience (global efficiency after attack) and wiring cost (mean degree) of the network.
At 10 days and 3 weeks after stroke, resilience was similar in patients and controls. However, at 3 months, although motor function had fully recovered, resilience to clinically representative simulated lesions was higher compared to controls (cortical lesion
=0.012; subcortical:
=0.009; cortico-subcortical:
=0.009). Similar results were found after random (
=0.012) and targeted (
=0.015) attacks.
Our results suggest that, in this highly selected cohort of patients with lesions restricted to the primary motor cortex, brain networks reconfigure to increase resilience to future insults. Lesion simulation is an innovative approach, which may have major implications for stroke therapy. Individualized neuromodulation strategies could be developed to foster resilient network reconfigurations after a first stroke to limit the consequences of future attacks.
After stroke restricted to the primary motor cortex (M1), it is uncertain whether network reorganization associated with recovery involves the periinfarct or more remote regions. We studied 16 ...patients with focal M1 stroke and hand paresis. Motor function and resting-state MRI functional connectivity (FC) were assessed at three time points: acute (<10 days), early subacute (3 weeks), and late subacute (3 months). FC correlates of recovery were investigated at three spatial scales, (i) ipsilesional non-infarcted M1, (ii) core motor network (M1, premotor cortex (PMC), supplementary motor area (SMA), and primary somatosensory cortex), and (iii) extended motor network including all regions structurally connected to the upper limb representation of M1. Hand dexterity was impaired only in the acute phase (P = 0.036). At a small spatial scale, clinical recovery was more frequently associated with connections involving ipsilesional non-infarcted M1 (Odds Ratio = 6.29; P = 0.036). At a larger scale, recovery correlated with increased FC strength in the core network compared to the extended motor network (rho = 0.71;P = 0.006). These results suggest that FC changes associated with motor improvement involve the perilesional M1 and do not extend beyond the core motor network. Core motor regions, and more specifically ipsilesional non-infarcted M1, could hence become primary targets for restorative therapies.
Abstract only Introduction: Imaging studies are used to guide patient selection for acute stroke treatment. Perfusion CT (pCT) is widely used to identify the acute ischemic core and penumbra, but the ...prediction of the final infarct remains challenging. With the advent of machine learning, algorithms learning the prediction of the final lesion from imaging data collected in the acute phase have been proposed. We aimed to investigate whether machine learning methods that integrate prior ischemic core segmentation improve the prediction of the final infarct after stroke. Methodology: We retrospectively included all stroke patients admitted to the Geneva University Hospital for intravenous and/or endovascular treatment from 01.2016 to 12.2017. All patients had acute pCT and follow-up MRI. An Attention-Gated 3D Unet was used as the baseline model on which the effect of access to a threshold-based ischemic core segmentation was tested. To ensure the efficient integration of information contained in voxels from the ischemic core, we extended the baseline model with a bayesian skip connection allowing only the prior to bypass most of the network. This modifies the model’s task to predict divergence from the prior representation. All models were evaluated for the prediction of the final infarct on follow-up MRI, given acute pCT maps as input. The output of each model was compared to finals lesions manually delineated by expert neurologists. Dice score was used to assess performance. Results: A total of 144 patients were included. Median hypoperfused tissue volume (Tmax > 6s) was 60 ml 17-134, median ischemic core (relative CBF < 38%) volume was 23 ml 17-33 and median final infarct volume was 13 ml 3-38. Dice score for the threshold based ischemic core segmentation was 0.1. The baseline model with and without prior segmentation as input achieved a Dice score of 0.19. Adding the proposed bayesian skip connection lead to a more efficient integration of the prior segmentation ensuring faster convergence and better performance with a final Dice score of 0.21. Conclusion: The evaluated deep learning model can effectively leverage the information contained in a prior segmentation of the ischemic core to enhance the learning process and improve the prediction of the final infarct after stroke.
Abstract only Background and Purpose: After stroke restricted to the primary motor cortex (M1), it is uncertain whether network reorganization associated with motor recovery involves the periinfarct ...or more remote brain regions. In humans, the challenge is to recruit patients with similar lesions in size and location. Methods: We studied 16 patients with focal M1 stroke and hand paresis. Motor function and resting-state MRI functional connectivity (FC) were studied at three time points: acute (<10 days), early subacute (3 weeks), and late subacute (3 months). FC correlates of motor recovery were investigated at three spatial scales, i) ipsilesional non-infarcted M1, ii) core motor network (including M1, premotor cortex (PMC), supplementary motor area (SMA), and primary somatosensory cortex), and iii) extended motor network including all regions structurally connected to the upper limb representation of M1. Results: Hand dexterity was impaired only in the acute phase ( P =0.036). At a small spatial scale, improved dexterity was associated with increased FC involving mainly the ipsilesional non-infarcted M1 and contralesional motor regions (cM1: rho=0.732; P =0.004; cPMC: rho=0.837, P <0.001; cSMA: rho=0.736; P =0.004). At a larger scale, motor recovery correlated with the relative increase in total FC strength in the core motor network compared to the extended motor network (rho=0.71; P =0.006). Conclusions: FC changes associated with motor improvement involve the perilesional M1 and do not extend beyond the core motor network. The ipsilesional non-infarcted M1 and core motor regions could hence be primary targets for future restorative therapies.
Abstract only Introduction: Endovascular treatment (EVT) is the therapy of choice, in patients with unknown stroke onset (unwitnessed and wake-up strokes) and large vessel occlusion (LVO) with a ...favorable perfusion pattern. Whether bridging therapy (intravenous thrombolysis (IVT) and EVT) is superior to EVT alone remains unknown. Material and Methods: We retrospectively included all patients admitted to the Geneva University Hospital from 01.2016 to 06.2020 with i) stroke of unknown onset, due to ii) anterior circulation occlusion, with iii) favorable CT perfusion pattern based on the DEFUSE criteria (ischemic core volume< 70ml; mismatch ratio >= 1.8 and mismatch volume >= 15ml), and iv) treated < 4.5 hours after symptom recognition. As a standard of care, the patients fulfilling these inclusion criteria were treated with EVT and IVT or EVT alone when IVT was contraindicated. Outcome measures were any intracerebral bleeding (symptomatic or asymptomatic), mortality and favorable outcome (mRS 0-1) at three months. Results: 32 patients were included (17 treated with EVT alone and 15 with EVT and IVT). Mean age was 69±18 yo. Median NIHSS was 16 (IQR 12-20) and median time from symptom recognition to treatment was 184 (146-226) minutes. Median hypoperfused tissue volume (Tmax > 6s) was 119 ml (80-151) and infarcted core (CBF ratio <30%) 8 ml (0-27). After propensity score weighting, bridging therapy was not associated with an increased risk of intracerebral bleeding (p=0.72) or mortality (p=0.55). The proportion of favorable outcomes at three months was similar between treatment groups (p=0.78). Conclusion: These results suggest that IVT before EVT is a safe therapeutic option in patients with unknown stroke onset selected on perfusion imaging and treated <4.5 hours after symptom recognition. Early administration of IVT may be particularly relevant before interhospital transfer to a comprehensive stroke center for EVT.
Objective
The aim was to evaluate, in patients with atrial fibrillation (AF) and acute ischemic stroke, the association of prior anticoagulation with vitamin K antagonists (VKAs) or direct oral ...anticoagulants (DOACs) with stroke severity, utilization of intravenous thrombolysis (IVT), safety of IVT, and 3‐month outcomes.
Methods
This was a cohort study of consecutive patients (2014–2019) on anticoagulation versus those without (controls) with regard to stroke severity, rates of IVT/mechanical thrombectomy, symptomatic intracranial hemorrhage (sICH), and favorable outcome (modified Rankin Scale score 0–2) at 3 months.
Results
Of 8,179 patients (mean SD age, 79.8 9.6 years; 49% women), 1,486 (18%) were on VKA treatment, 1,634 (20%) on DOAC treatment at stroke onset, and 5,059 controls. Stroke severity was lower in patients on DOACs (median National Institutes of Health Stroke Scale 4, interquartile range 2–11) compared with VKA (6, 2–14) and controls (7, 3–15, p < 0.001; quantile regression: β −2.1, 95% confidence interval CI −2.6 to −1.7). The IVT rate in potentially eligible patients was significantly lower in patients on VKA (156 of 247 63%; adjusted odds ratio aOR 0.67; 95% CI 0.50–0.90) and particularly in patients on DOACs (69 of 464 15%; aOR 0.06; 95% CI 0.05–0.08) compared with controls (1,544 of 2,504 74%). sICH after IVT occurred in 3.6% (2.6–4.7%) of controls, 9 of 195 (4.6%; 1.9–9.2%; aOR 0.93; 95% CI 0.46–1.90) patients on VKA and 2 of 65 (3.1%; 0.4–10.8%, aOR 0.56; 95% CI 0.28–1.12) of those on DOACs. After adjustments for prognostic confounders, DOAC pretreatment was associated with a favorable 3‐month outcome (aOR 1.24; 1.01–1.51).
Interpretation
Prior DOAC therapy in patients with AF was associated with decreased admission stroke severity at onset and a remarkably low rate of IVT. Overall, patients on DOAC might have better functional outcome at 3 months. Further research is needed to overcome potential restrictions for IVT in patients taking DOACs. ANN NEUROL 2021;89:42–53
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