Vessel Wall Imaging Features of Spontaneous Intracranial Carotid Artery Dissection.

BACKGROUND AND OBJECTIVES: Intracranial dissection is an important cause of stroke often with nonspecific angiographic features. Vessel wall imaging (VWI) can detect dissections, but intracranial applications remain unvalidated by pathologic specimens. We sought to determine the ability of VWI to identify the rarely reported spontaneous intracranial carotid dissection (sICD) guided by postmortem validation. METHODS: VWI features of sICD, validated by postmortem specimen analysis in 1 patient, included luminal enhancement within a hypoenhancing outer wall, narrowing the mid to distal ophthalmic (C6) segment, relatively sparing the communicating (C7) segment. VWI examinations were reviewed to identify patients (1) with matching imaging features, (2) no evidence of other vasculopathies (i.e., inflammatory, intracranial atherosclerotic disease [ICAD]), and (3) adequate image quality. These sICD VWI features were compared with those in patients with known ICAD causing similar narrowing of C6 and relative sparing of C7 by a Fisher exact test accounting for multiple samples. RESULTS: Among 407 VWI examinations, 8 patients were identified with 14 sICDs, all women aged 30-56 years, 6 (75%) bilateral. All patients with sICD had risk factors of dissection (e.g., recently postpartum, fibromuscular dysplasia, and hypertension) and 3 (37.5%) had intracranial dissections elsewhere. Seven (87.5%) were diagnosed as moyamoya syndrome on initial angiography. Enhancing lesions varied from thin flap-like defects (n = 6) to thick tissue along the superolateral wall of the internal carotid artery, within the hypoenhancing outer wall. Compared with 10 intracranial carotid plaques in 8 patients with ICAD, sICD demonstrated stronger (84.6% vs 20.0%, p = 0.003-0.025) and more homogeneous (61.5% vs 0.0%, p = 0.005-0.069) enhancement and less positive remodeling (0.0% vs 60.0%, p = 0.004-0.09). T1 hyperintensity was identified in 5 sICDs in 3 patients but not identified in ICAD. Three patients with serial imaging (8- to 39.8-month maximum intervals) revealed little to no changes in stenosis, wall thickening, or enhancement. DISCUSSION: sICD is distinguishable on VWI from ICAD by enhancement characteristics, less positive remodeling, and clinical parameters. These VWI features should raise suspicion especially in young women with risk factors of dissection. Temporal stability and a lack of T1 hyperintensity should not discourage diagnosing sICD.

Alternate Day Fasting Leads to Improved Post-Stroke Motor Recovery in Mice.

BACKGROUND: Caloric restriction promotes neuroplasticity and recovery after neurological injury. In mice, we tested the hypothesis that caloric restriction can act post-stroke to enhance training-associated motor recovery. METHODS: Mice were trained to perform a skilled prehension task. We then induced a photothrombotic stroke in the caudal forelimb area, after which we retrained animals on the prehension task following an 8-day delay. Mice underwent either ad libitum feeding or alternate day fasting beginning 1-day after stroke and persisting for either 7 days or the entire post-stroke training period until sacrifice. RESULTS: Prior studies have shown that post-stroke recovery of prehension can occur if animals receive rehabilitative training during an early sensitive period but is incomplete if rehabilitative training is delayed. In contrast, we show complete recovery of prehension, despite a delay in rehabilitative training, when mice underwent alternate day fasting beginning 1-day post-stroke and persisting for either 7 days or the entire post-stroke training period until sacrifice. Recovery was independent of weight loss. Stroke volumes were similar across groups. CONCLUSIONS: Post-stroke caloric restriction led to recovery of motor function independent of a protective effect on stroke volume. Prehension recovery improved even after ad libitum feeding was reinstituted suggesting that the observed motor recovery was not merely a motivational response. These data add to the growing evidence that post-stroke caloric restriction can enhance recovery.

Bringing High-Dose Neurorestorative Behavioral Training Into the Acute Stroke Unit.

ABSTRACT: Stroke remains common and is a leading cause of adult disability. While there have been enormous system changes for the diagnosis and delivery of hyperacute stroke treatments at comprehensive stroke centers, few advances have been made in those same centers for treatments focused on behavioral recovery and brain repair. Specifically, during the early hospital period, there is a paucity of approaches available for reduction of impairment beyond what is expected from spontaneous biological recovery. Thus, patients in the early stroke recovery period are not receiving the kind of training needed, at the requisite intensity and dose, to exploit a potential critical period of heightened brain plasticity that could maximize true recovery instead of just compensation. Here, we describe an ongoing pilot program to reconfigure the acute stroke unit experience to allow for a new emphasis on brain repair. More specifically, we have introduced a novel room-based video-gaming intervention; restorative neuroanimation, into the acute stroke hospital setting. This new intervention provides the opportunity for an extra hour(s) of high-intensity neurorestorative behavioral treatment that is complementary to conventional rehabilitation. To accomplish this, system redesign was required to insert this new treatment into the patient day, to properly stratify patients behaviorally and physiologically for the treatment, to optimize the digital therapeutic approach itself, and to maintain the impairment reduction after discharge.

Providers' Perceptions of Neurology Care Delivered Through Telemedicine Technology.

Background: The COVID-19 pandemic and subsequent acceleration of telemedicine usage allowed many neurologists to trial telemedicine for neurological care. The purpose of this study is to explore neurology providers' experiences with delivering telemedicine care during the COVID-19 pandemic. Methods: Semistructured video interviews were conducted with 27 neurology providers who practice at a single, urban academic center. Interviews were transcribed and analyzed for content and themes. Results: Five major themes were identified: virtual examination subspecialty differences, tips and tricks for the virtual examination, improved infrastructure needs, future technologies that could support the virtual examination, and preferences for the postpandemic telemedicine protocol. Subspecialists who described their visits as more focused on behavioral examination and obtaining patient history reported fewer limitations with delivering neurological care through telemedicine platforms. Conclusions: The implementation of a telemedicine system should reflect the needs of each neurology subspecialty. Funding is needed to improve logistical infrastructure for health providers' telemedicine visits, such as technical and administrative assistance, as well as creation and testing of technologies to support physical examination in the virtual environment.

In Vivo Formation and Tracking of π-Peptide Nanostructures.

The photophysics associated with the self-assembly of π-peptide molecules into 1-D nanostructures has been well-established, thus revealing the creation of nanoscale electronic conduits in aqueous media. Such materials have therapeutic potential in many biomedical applications. In this work, we report the in vivo deployment of these π-peptide nanostructures in brain tissue using photothrombotic stroke as a model application. A test peptide was used for brain injections, and the nanostructures formed were visualized with electron microscopy. A new peptide bearing a low-energy fluorescence dye was prepared to facilitate direct visualization of π-peptide localization in the brain cavity by way of fluorescence microscopy. This work demonstrates feasibility for in vivo application of π-peptide nanostructures toward pressing biomedical challenges.

Telemedicine Services for the Delivery of Specialty Home-Based Neurological Care.

Introduction: The COVID-19 pandemic accelerated the adoption of telemedicine services for the delivery of outpatient neurological care. We sought to understand perceptions and the acceptance of this technology by neurology specialists during the proliferation of telemedicine services into their outpatient practices. Methods: We adapted the Telehealth Usability Questionnaire for neurological care via telemedicine. Our 29-item questionnaire evaluated the telemedicine system in three domains: quality of the telemedicine platform, ability to conduct a sufficient neurological examination, and overall system confidence. The survey was distributed to 88 clinical neurology faculty in the Johns Hopkins Health System. Responses were collapsed into "Favorable," "Neutral," and "Unfavorable." Within each domain, responses to individual questions were analyzed by neurology subspecialty using descriptive statistics. Results: We received completed surveys from 46 of the 88 (52%) neurology faculty. Of those, most reported favorable comfort with the current platform (98%), ease of use (73%), and quality (80%). However, responses indicated only average ability to troubleshoot telemedicine platform issues when they occurred (55%) and to complete an entire neurological examination (52%). Subspecialty comparisons revealed differences in diagnostic confidence; 30% of neuromuscular faculty indicated that they could make accurate neurological diagnoses through a tele-examination as opposed to ≥84% for other specialties. Conclusions: The use of telemedicine services for the delivery of outpatient neurological care is feasible and acceptable to most neurologists, although diagnostic confidence compared with in-person visits may be reduced and differs by subspecialty. Improvements in technological infrastructure and care models are needed to advance telemedicine neurological care delivery. Our data also suggest that a larger multicenter investigation of telemedicine use post-pandemic would be useful.

Transcranial photoacoustic characterization of neurovascular physiology during early-stage photothrombotic stroke in neonatal pigletsin vivo.

OBJECTIVE: Perinatal ischemic stroke is estimated to occur in 1/2300-1/5000 live births, but early differential diagnosis from global hypoxia-ischemia is often difficult. In this study, we tested the ability of a hand-held transcranial photoacoustic (PA) imaging probe to non-invasively detect a focal photothrombotic stroke (PTS) within 2 h of stroke onset in a gyrencephalic piglet brain. APPROACH: About 17 stroke lesions of approximately 1 cm2area were introduced randomly in anterior or posterior cortex via the light/dye PTS technique in anesthetized neonatal piglets (n= 11). The contralateral non-ischemic region served as control tissue for discrimination contrast for the PA hemoglobin metrics: oxygen saturation, total hemoglobin (tHb), and individual quantities of oxygenated and deoxygenated hemoglobin (HbO2and HbR). MAIN RESULTS: The PA-derived tissue oxygen saturation at 2 h yielded a significant separation between control and affected regions-of-interest (p< 0.0001), which were well matched with 24 h post-stroke cerebral infarction confirmed in the triphenyltetrazolium chloride-stained image. The quantity of HbO2also displayed a significant contrast (p= 0.021), whereas tHb and HbR did not. The analysis on receiver operating characteristic curves and multivariate data analysis also agreed with the results above. SIGNIFICANCE: This study shows that a hand-held transcranial PA neuroimaging device can detect a regional thrombotic stroke in the cerebral cortex of a neonatal piglet. In particular, we conclude that the oxygen saturation metric can be used alone to identify regional stroke lesions. The lack of change in tHb may be related to arbitrary hand-held imaging configuration and/or entrapment of red blood cells within the thrombotic stroke.

Enhanced Spontaneous Motor Recovery After Stroke in Mice Treated With Cerebrolysin.

BACKGROUND: Motor recovery after stroke in humans and in rodent models is time sensitive. Recovery in patients is a result of biological spontaneous recovery via endogenous repair mechanisms and is likely improved by enhancing the synaptic plasticity required for endogenous repair. Cerebrolysin is a polypeptide preparation known to enhance neuroplasticity and may improve recovery in patients. In mice, we tested the hypothesis that Cerebrolysin can act poststroke to enhance both spontaneous and training-associated motor recovery. METHODS: Mice were trained to perform a skilled prehension task. We then induced a photothrombotic stroke in the caudal forelimb area, after which we retrained animals on the prehension task in the presence or absence of Cerebrolysin after a 2-day or 8-day delay. Mice received daily intraperitoneal Cerebrolysin or saline injections starting poststroke day 1 or poststroke day 7. RESULTS: Prior studies showed that poststroke recovery of prehension can occur if animals receive rehabilitative training during an early sensitive period but is incomplete if rehabilitative training is delayed. In contrast, we show complete recovery of prehension, despite a delay in rehabilitative training, when mice receive daily Cerebrolysin administration starting on poststroke day 1 or on poststroke day 8. When Cerebrolysin is given on poststroke day 1, recovery occurred even in the absence of training. Stroke volumes were similar across groups. CONCLUSIONS: Poststroke Cerebrolysin administration leads to recovery of motor function independent of rehabilitative training without a protective effect on stroke volume. This is one of the first demonstrations of training-independent motor recovery in rodent stroke models.

Comparing a Novel Neuroanimation Experience to Conventional Therapy for High-Dose Intensive Upper-Limb Training in Subacute Stroke: The SMARTS2 Randomized Trial.

BACKGROUND: Evidence from animal studies suggests that greater reductions in poststroke motor impairment can be attained with significantly higher doses and intensities of therapy focused on movement quality. These studies also indicate a dose-timing interaction, with more pronounced effects if high-intensity therapy is delivered in the acute/subacute, rather than chronic, poststroke period. OBJECTIVE: To compare 2 approaches of delivering high-intensity, high-dose upper-limb therapy in patients with subacute stroke: a novel exploratory neuroanimation therapy (NAT) and modified conventional occupational therapy (COT). METHODS: A total of 24 patients were randomized to NAT or COT and underwent 30 sessions of 60 minutes time-on-task in addition to standard care. The primary outcome was the Fugl-Meyer Upper Extremity motor score (FM-UE). Secondary outcomes included Action Research Arm Test (ARAT), grip strength, Stroke Impact Scale hand domain, and upper-limb kinematics. Outcomes were assessed at baseline, and days 3, 90, and 180 posttraining. Both groups were compared to a matched historical cohort (HC), which received only 30 minutes of upper-limb therapy per day. RESULTS: There were no significant between-group differences in FM-UE change or any of the secondary outcomes at any timepoint. Both high-dose groups showed greater recovery on the ARAT (7.3 ± 2.9 points; P = .011) but not the FM-UE (1.4 ± 2.6 points; P = .564) when compared with the HC. CONCLUSIONS: Neuroanimation may offer a new, enjoyable, efficient, and scalable way to deliver high-dose and intensive upper-limb therapy.

Advances and challenges in stroke rehabilitation.

Stroke remains a leading cause of adult disability and the demand for stroke rehabilitation services is growing. Substantial advances are yet to be made in stroke rehabilitation practice to meet this demand and improve patient outcomes relative to current care. Several large intervention trials targeting motor recovery report that participants' motor performance improved, but to a similar extent for both the intervention and control groups in most trials. These neutral results might reflect an absence of additional benefit from the tested interventions or the many challenges of designing and doing large stroke rehabilitation trials. Strategies for improving trial quality include new approaches to the selection of patients, control interventions, and endpoint measures. Although stroke rehabilitation research strives for better trials, interventions, and outcomes, rehabilitation practices continue to help patients regain independence after stroke.

Evaluating Skilled Prehension in Mice Using an Auto-Trainer.

We describe a method to introduce naïve mice to a novel prehension (reach-to-grasp) task. Mice are housed singly in cages with a frontal slot that permits the mouse to reach out of its cage and retrieve food pellets. Minimal food restriction is employed to encourage the mice to perform the food retrieval from the slot. As the mice begin to associate coming to the slot for food, the pellets are manually pulled away to stimulate extension and pronation of their paw to grasp and retrieve the pellet through the frontal slot. When the mice begin to reach for the pellets as they arrive at the slot, the behavioral assay can be performed by measuring the rate at which they successfully grasp and retrieve the desired pellet. They are then introduced to an auto-trainer that automates both the process of providing food pellets for the mouse to grasp, and the recording of successful and failed reaching and grasping attempts. This allows for the collection of reaching data for multiple mice with minimal effort, to be used in experimental analysis as appropriate.

Temporal course and implications of intracranial atherosclerotic plaque enhancement on high-resolution vessel wall MRI.

PURPOSE: Little is known about the natural history of intracranial atherosclerotic plaque enhancement and its clinical implications. Our objective was to investigate the value of follow-up high-resolution contrast-enhanced vessel wall MRI (VWMRI) for classifying culprit plaques in patients with intracranial atherosclerotic disease (ICAD). METHODS: Fourteen patients with symptomatic ICAD (50% females; median age 48 years) underwent serial 3T VWMRI. Fifty-five plaques were identified and graded based on the likelihood of having caused the ischemic event (non-culprit, indeterminate, culprit) and degree of enhancement (0, 1, 2) at baseline and follow-up (median follow-up, 140 days). For accuracy analysis, plaque enhancement at baseline and stable or increasing plaque enhancement at follow-up was tested to identify a culprit plaque, and areas under the receiver operating characteristic curves (AUCs) were compared. RESULTS: In 37/55 (67.3%) plaques, enhancement grade remained unchanged. Lack of enhancement was only seen in non-culprit plaques at baseline, and none developed enhancement over time. Enhancement never changed more than one grade. Thirty-seven percent (10/27) of non-culprit plaques that enhanced decreased in enhancement grade at follow-up, but no culprit plaques decreased in enhancement. AUC of baseline and follow-up plaque enhancement combined was significantly larger than AUC of baseline plaque enhancement alone to identify culprit plaques (0.733 vs. 0.567, p = 0.0001). CONCLUSION: Contrast enhancement of ICAD can persist months after the ischemic event. Lack of enhancement at baseline or a decrease in enhancement at follow-up suggests that the plaque is not culprit. Persistent enhancement from baseline to follow-up improves accuracy in identifying culprit plaques.

Should We Care About Early Post-Stroke Rehabilitation? Not Yet, but Soon.

PURPOSE OF REVIEW: Studies in humans and animal models show that most recovery from impairment occurs in the first 1-3 months after stroke as a result of both spontaneous recovery as well as increased responsiveness to enriched environments and training. Improvement from impairment is attributable to a short-lived "sensitive period" of post-stroke plasticity defined by unique genetic, physiological, and structural events. Unfortunately, rehabilitative interventions in humans have not been able to exploit this sensitive period similar to that seen in animal models. Here, we review these data and suggest a path forward. RECENT FINDINGS: Pre-clinical data reveal underlying mechanisms that define the post-stroke sensitive period. These data are then discussed in the context of the spontaneous post-stroke recovery described in humans. Future work will need to capitalize on unique interactions between the sensitive period, spontaneous recovery, and novel types of rehabilitative interventions.

Safety of intravenous alteplase within 4.5 hours for patients awakening with stroke symptoms.

BACKGROUND: Up to 25% of acute stroke patients first note symptoms upon awakening. We hypothesized that patients awaking with stroke symptoms may be safely treated with intravenous alteplase (IV tPA) using non-contrast head CT (NCHCT), if they meet all other standard criteria. METHODS: The SAfety of Intravenous thromboLytics in stroke ON awakening (SAIL ON) was a prospective, open-label, single treatment arm, pilot safety trial of standard dose IV tPA in patients who presented with stroke symptoms within 0-4.5 hours of awakening. From January 30, 2013, to September 1, 2015, twenty consecutive wakeup stroke patients selected by NCHCT were enrolled. The primary outcome was symptomatic intracerebral hemorrhage (sICH) in the first 36 hours. Secondary outcomes included NIH stroke scale (NIHSS) at 24 hours; and modified Rankin Score (mRS), NIHSS, and Barthel index at 90 days. RESULTS: The average age was 65 years (range 47-83); 40% were women; 50% were African American. The average NIHSS was 6 (range 4-11). The average time from wake-up to IV tPA was 205 minutes (range 114-270). The average time from last known well to IV tPA was 580 minutes (range 353-876). The median mRS at 90 days was 1 (range 0-5). No patients had sICH; two of 20 (10%) had asymptomatic ICH on routine post IV tPA brain imaging. CONCLUSIONS: Administration of IV tPA was feasible and may be safe in wakeup stroke patients presenting within 4.5 hours from awakening, screened with NCHCT. An adequately powered randomized clinical trial is needed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01643902.

Paradoxical Motor Recovery From a First Stroke After Induction of a Second Stroke: Reopening a Postischemic Sensitive Period.

BACKGROUND AND OBJECTIVE: Prior studies have suggested that after stroke there is a time-limited period of increased responsiveness to training as a result of heightened plasticity-a sensitive period thought to be induced by ischemia itself. Using a mouse model, we have previously shown that most training-associated recovery after a caudal forelimb area (CFA) stroke occurs in the first week and is attributable to reorganization in a medial premotor area (AGm). The existence of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and promote full recovery from the first stroke. To test this prediction, we induced a second stroke in the AGm of mice with incomplete recovery after a first stroke in CFA. METHODS: Mice were trained to perform a skilled prehension (reach-to-grasp) task to an asymptotic level of performance, after which they underwent photocoagulation-induced stroke in CFA. After a 7-day poststroke delay, the mice were then retrained to asymptote. We then induced a second stroke in the AGm, and after only a 1-day delay, retrained the mice. RESULTS: Recovery of prehension was incomplete when training was started after a 7-day poststroke delay and continued for 19 days. However, a second focal stroke in the AGm led to a dramatic response to 9 days of training, with full recovery to normal levels of performance. CONCLUSIONS: New ischemia can reopen a sensitive period of heightened responsiveness to training and mediate full recovery from a previous stroke.

Patterns and Implications of Intracranial Arterial Remodeling in Stroke Patients.

BACKGROUND AND PURPOSE: Preliminary studies suggest that intracranial arteries are capable of accommodating plaque formation by remodeling. We sought to study the ability and extent of intracranial arteries to remodel using 3-dimensional high-resolution black blood magnetic resonance imaging and investigate its relation to ischemic events. METHODS: Forty-two patients with cerebrovascular ischemic events underwent 3-dimensional time-of-flight magnetic resonance angiography and contrast-enhanced black blood magnetic resonance imaging examinations at 3 T for intracranial atherosclerotic disease. Each plaque was classified by location (eg, posterior versus anterior circulation) and its likelihood to have caused a stroke identified on magnetic resonance imaging (culprit, indeterminate, or nonculprit). Lumen area, outer wall area, and wall area were measured at the lesion and reference sites. Plaque burden was calculated as wall area divided by outer wall area. The arterial remodeling ratio (RR) was calculated as outer wall area at the lesion site divided by outer wall area at the reference site after adjusting for vessel tapering. Arterial remodeling was categorized as positive if RR>1.05, intermediate if 0.95≤RR≤1.05, and negative if RR<0.95. RESULTS: One hundred and thirty-seven plaques were identified in 42 patients (37% [50] posterior and 63% [87] anterior). Compared with anterior circulation plaques, posterior circulation plaques had a larger plaque burden (77.7±15.7 versus 69.0±14.0; P=0.008), higher RR (1.14±0.38 versus 0.95±0.32; P=0.002), and more often exhibited positive remodeling (54.0% versus29.9%; P=0.011). Positive remodeling was marginally associated with downstream stroke presence when adjusted for plaque burden (odds ratio 1.34, 95% confidence interval: 0.99-1.81). CONCLUSIONS: Intracranial arteries remodel in response to plaque formation, and posterior circulation arteries have a greater capacity for positive remodeling and, consequently, may more likely elude angiographic detection. Arterial remodeling may provide insight into stroke risk.

Fluoxetine Maintains a State of Heightened Responsiveness to Motor Training Early After Stroke in a Mouse Model.

BACKGROUND AND PURPOSE: Data from both humans and animal models suggest that most recovery from motor impairment after stroke occurs in a sensitive period that lasts only weeks and is mediated, in part, by an increased responsiveness to training. Here, we used a mouse model of focal cortical stroke to test 2 hypotheses. First, we investigated whether responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. METHODS: Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area. The mice were then retrained after a 1- or 7-day delay with and without fluoxetine. RESULTS: Recovery of prehension after a caudal forelimb area stroke was complete if training was initiated 1 day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine seemed to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. CONCLUSIONS: There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke.