Pratik Y. Chhatbar

Corticospinal tract lesion load: An imaging biomarker for stroke motor outcomes

The aim of this work was to investigate whether an imaging measure of corticospinal tract (CST) injury in the acute phase can predict motor outcome at 3 months in comparison to clinical assessment of initial motor impairment.

An artery-specific fluorescent dye for studying neurovascular coupling

We demonstrate that Alexa Fluor 633 hydrazide (Alexa Fluor 633) selectively labels neocortical arteries and arterioles by binding to elastin fibers. We measured sensory stimulus–evoked arteriole dilation dynamics in mouse, rat and cat visual cortex using Alexa Fluor 633 together with neuronal activity using calcium indicators or blood flow using fluorescein dextran. Arteriole dilation decreased fluorescence recorded from immediately underlying neurons, representing a potential artifact during neuronal functional imaging experiments.

Neural correlates of single-vessel haemodynamic responses in vivo

Neural activation increases blood flow locally. This vascular signal is used by functional imaging techniques to infer the location and strength of neural activity1,2. However, the precise spatial scale over which neural and vascular signals are correlated is unknown. Furthermore, the relative role of synaptic and spiking activity in driving hemodynamic signals is controversial3-9. Prior studies recorded local field potentials (LFPs) as a measure of synaptic activity together with spiking activity and low-resolution hemodynamic imaging. Here we used two-photon microscopy to measure sensory-evoked responses of individual blood vessels (dilation, blood velocity) while imaging synaptic and spiking activity in the surrounding tissue using fluorescent glutamate and calcium sensors. In cat primary visual cortex, where neurons are clustered by their preference for stimulus orientation, we discovered new maps for excitatory synaptic activity, which were organized similar to spiking activity but were less selective for stimulus orientation and direction. We generated tuning curves for individual vessel responses for the first time and found that parenchymal vessels in cortical layer 2/3 were orientation selective. Neighboring penetrating arterioles had different orientation preferences. Pial surface arteries in cats, as well as surface arteries and penetrating arterioles in rat visual cortex (where orientation maps do not exist10), responded to visual stimuli but had no orientation selectivity. We integrated synaptic or spiking responses around individual parenchymal vessels in cats and established that the vascular and neural responses had the same orientation preference. However, synaptic and spiking responses were more selective than vascular responses—vessels frequently responded robustly to stimuli that evoked little to no neural activity in the surrounding tissue. Thus, local neural and hemodynamic signals were partly decoupled. Together, these results indicate that intrinsic cortical properties, such as propagation of vascular dilation between neighboring columns, need to be accounted for when decoding hemodynamic signals.

Transcranial Direct Current Stimulation Post-Stroke Upper Extremity Motor Recovery Studies Exhibit a Dose-Response Relationship.

BACKGROUND AND PURPOSE Transcranial direct current stimulation (tDCS) has shown mixed results in post-stroke motor recovery, possibly because of tDCS dose differences. The purpose of this meta-analysis was to explore whether the outcome has a dose-response relationship with various dose-related parameters. METHODS The literature was searched for double-blind, randomized, sham-controlled clinical trials investigating the role of tDCS (≥5 sessions) in post-stroke motor recovery as measured by the Fugl-Meyer Upper Extremity (FM-UE) scale. Improvements in FM-UE scores were compared between active and sham groups by calculating standardized mean differences (Hedges g) to derive a summary effect size. Inverse-variance-weighted linear meta-regression across individual studies was performed between various tDCS parameters and Hedges g to test for dose-response relationships. RESULTS Eight studies with total of 213 stroke subjects were included. Summary Hedges g was statistically significant in favor of the active group (Hedges g = 0.61, p = 0.02) suggesting moderate effect. Specifically, studies that used bihemispheric tDCS montage (Hedges g = 1.30, p = 0.08) or that recruited chronic stroke patients (Hedges g = 1.23, p = 0.02) showed large improvements in the active group. A positive dose-response relationship was found with current density (p = 0.017) and charge density (p = 0.004), but not with current amplitude. Moreover, a negative dose-response relationship was found with electrode size (p < 0.001, smaller electrodes were more effective). CONCLUSIONS Our meta-analysis and meta-regression results suggest superior motor recovery in the active group when compared to the sham group and dose-response relationships relating to electrode size, charge density and current density. These results need to be confirmed in future dedicated studies.

Data Synthesis in Meta-Analysis may Conclude Differently on Cognitive Effect From Transcranial Direct Current Stimulation

We read, with great interest, the newly published article in Brain Stimulation Journal by Dr. Horvath and his colleagues [1] suggesting that single-session transcranial direct current stimulation (tDCS) has no cognitive effect on healthy populations based on the metaanalysis of 59 published studies. The authors did a commendable job in searching literature and aggregating data. Their article summarized the cognitive effect from tDCS on humans. However, the approach used by the authors in data synthesis may have missed uncovering the potential cognitive effect by tDCS. Two issues are relevant for accurately calculating the summary effect size of stimulation. First, the effect size (specifically, Hedge’s g) calculated from post-active (and post-sham) stimulation outcome scores do not always reflect the effects of active stimulation. The issue raised by using only post-active or post-sham stimulation outcome scores is two-fold:

Improved blood velocity measurements with a hybrid image filtering and iterative Radon transform algorithm

Neural activity leads to hemodynamic changes which can be detected by functional magnetic resonance imaging (fMRI). The determination of blood flow changes in individual vessels is an important aspect of understanding these hemodynamic signals. Blood flow can be calculated from the measurements of vessel diameter and blood velocity. When using line-scan imaging, the movement of blood in the vessel leads to streaks in space-time images, where streak angle is a function of the blood velocity. A variety of methods have been proposed to determine blood velocity from such space-time image sequences. Of these, the Radon transform is relatively easy to implement and has fast data processing. However, the precision of the velocity measurements is dependent on the number of Radon transforms performed, which creates a trade-off between the processing speed and measurement precision. In addition, factors like image contrast, imaging depth, image acquisition speed, and movement artifacts especially in large mammals, can potentially lead to data acquisition that results in erroneous velocity measurements. Here we show that pre-processing the data with a Sobel filter and iterative application of Radon transforms address these issues and provide more accurate blood velocity measurements. Improved signal quality of the image as a result of Sobel filtering increases the accuracy and the iterative Radon transform offers both increased precision and an order of magnitude faster implementation of velocity measurements. This algorithm does not use a priori knowledge of angle information and therefore is sensitive to sudden changes in blood flow. It can be applied on any set of space-time images with red blood cell (RBC) streaks, commonly acquired through line-scan imaging or reconstructed from full-frame, time-lapse images of the vasculature.

Mobile health as a viable strategy to enhance stroke risk factor control: A systematic review and meta-analysis

BACKGROUND With the rapid growth worldwide in cell-phone use, Internet connectivity, and digital health technology, mobile health (mHealth) technology may offer a promising approach to bridge evidence-treatment gaps in stroke prevention. We aimed to evaluate the effectiveness of mHealth for stroke risk factor control through a systematic review and meta-analysis. METHODS We searched PubMed from January 1, 2000 to May 17, 2016 using the following keywords: mobile health, mHealth, short message, cellular phone, mobile phone, stroke prevention and control, diabetes mellitus, hypertension, hyperlipidemia and smoking cessation. We performed a meta-analysis of all eligible randomized control clinical trials that assessed a sustained (at least 6months) effect of mHealth. RESULTS Of 78 articles identified, 13 met eligibility criteria (6 for glycemic control and 7 for smoking cessation) and were included for the final meta-analysis. There were no eligible studies for dyslipidemia or hypertension. mHealth resulted in greater Hemoglobin A1c reduction at 6months (6 studies; 663 subjects; SMD: -0.44; 95% CI: [-0.82, -0.06], P=0.02; Mean difference of decrease in HbA1c: -0.39%; 95% CI: [-0.74, -0.04], P=0.03). mHealth also lead to relatively higher smoking abstinence rates at 6months (7 studies; 9514 subjects; OR: 1.54; 95% CI: [1.24, 1.90], P<0.0001). CONCLUSIONS Our meta-analysis supports that use of mHealth improves glycemic control and smoking abstinence rates.

Transcranial Direct Current Stimulation for Poststroke Motor Recovery: Challenges and Opportunities

There has been a renewed research interest in transcranial direct current stimulation (tDCS) as an adjunctive tool for poststroke motor recovery as it has a neuro‐modulatory effect on the human cortex. However, there are barriers towards its successful application in motor recovery as several scientific issues remain unresolved, including device‐related issues (ie, dose‐response relationship, safety and tolerability concerns, interhemispheric imbalance model, and choice of montage) and clinical trial‐related issues (ie, patient selection, timing of study, and choice of outcomes). This narrative review examines and discusses the existing challenges in using tDCS as a brain modulation tool in facilitating recovery after stroke. Potential solutions pertinent to using tDCS with the goal of harnessing the brains plasticity are proposed.

Mesenchymal Stem Cells Therapy in Stroke: A Systematic Review of Literature in Pre-Clinical and Clinical Research.

Exogenous stem cell therapy (SCT) has been recognized recently as a promising neuroregenerative strategy to augment recovery in stroke survivors. Mesenchymal stem cells (MSCs) are the primary source of stem cells used in the majority of both pre-clinical and clinical studies in stroke. In the absence of evidence-based guidelines on the use of SCT in stroke patients, understanding the progress of MSC research across published studies will assist researchers and clinicians in better achieving success in translating research. We conducted a systematic review on published literature using MSCs in both pre-clinical studies and clinical trials between 2008 and 2017 using the public databases PubMed and Ovid Medline, and the clinical trial registry (www.clinicaltrials.gov). A total of 78 pre-clinical studies and eight clinical studies were identified. While majority of the pre-clinical and clinical studies demonstrated statistically significant effects, the clinical significance of these findings was still unclear. Effect sizes could not be measured mainly due to reporting issues in pre-clinical studies, thus limiting our ability to compare results across studies quantitatively. The overall quality of both pre-clinical and clinical studies was sub-optimal. By conducting a systematic review of both pre-clinical and clinical studies on MSCs therapy in stroke, we assessed the quality of current evidence and identified several issues and gaps in translating animal studies to human trials. Addressing these issues and incorporating changes into future animal studies and human trials may lead to better success of stem cells-based therapeutics in the near future.

Poster 470: Safety and Tolerability of Transcranial Direct Current Stimulation to Stroke Patients – A Phase I Current Escalation Study

Disclosures: Wuwei Feng: I Have No Relevant Financial Relationships To Disclose Objective: A prior meta-analysis revealed that higher doses of transcranial direct current stimulation (tDCS) have a better poststroke upper-extremity motor recovery. While this finding suggests that currents greater than the typically used 2 mA may be more efficacious, the safety and tolerability of higher currents have not been assessed in stroke patients. We aim to assess the safety and tolerability of single session of up to 4 mA in stroke patients. Design: We adapted a traditional 3 + 3 study design with a current escalation schedule of 1>2>2.5>3>3.5>4 mA for this tDCS safety and tolerability study. Setting: Stroke rehabilitation center Participants: First-ever ischemic stroke patients with unilateral motor impairment with Fugl-Meyer upper extremity scale score <1⁄4 56/66. Interventions: We administered one 30-min session of bihemispheric montage tDCS and simultaneous customary occupational therapy to patients with first-ever ischemic stroke. Main Outcome Measures: We assessed safety with pre-defined stopping rules (second degree skin burn, clinical seizure; ADC abnormality or discontinuation from the study) and investigated tolerability through a questionnaire. Results: 18 patients completed the study. The currentwas escalated to 4 mA without meeting the pre-defined stopping rules or causing any major safety concern. 50% of patients experienced transient skin rednesswithout injury. No rise in temperature (range 26-35C)wasnoted and skin barrier function remained intact (i.e. body resistance >1KM). Conclusions: Our phase I safety study supports that single session of bihemispheric tDCS with current up to 4 mA is safe and tolerable in stroke patients. A phase II study to further test the safety and preliminary efficacy with multi-session tDCS at 4 mA (as compared with lower current and sham stimulation) is a logical next step. ClinicalTrials.gov Identifier: NCT02763826. Level of Evidence: Level I